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发表于 2020-3-30 22:06:21 | 显示全部楼层 |阅读模式
CHAPTER 54  Homocysteine Metabolism: Nutritional Modulation and Impact on Health and Disease
Alan L. Miller, ND, Gregory S. Kelly, ND, and Jessica Tran, ND
Introduction, 488
Homocysteine Metabolism, 488
Gender and Genetics, 488
Lifestyle, 489
Nutritional Relationships, 489
Renal Function, 493
Pharmaceutic Drug Effects on Homocysteine, 493 Impact of Homocysteine on Key Nutrients, 493
S-Adenosylmethionine, 493
Carnitine, 493
Chondroitin Sulfates, Glucosamine Sulfate, and Other
Sulfated Proteoglycans, 494
Coenzyme A, 494
Coenzyme Q10, 494
Creatine, 494
Epinephrine and Melatonin, 495
Phosphatidylcholine, 495
Taurine, 496
Clinical Applications, 496
Phase 2 Detoxication, 496
Heart Disease, 496
Peripheral Vascular Disease, 497
Stroke, 497
Pregnancy, 497
Neurologic and Mental Disorders, 498
Diabetes Mellitus, 498
Rheumatoid Arthritis, 499
Psoriasis, 499
Kidney Failure, 499
Alcoholism and Ethanol Ingestion, 499
Gout, 499
Osteoporosis, 500
Autism, 500
Drug-Induced Hyperhomocysteinemia, 500
Diagnostic Considerations, 500
Therapeutic Considerations, 500
Therapeutic Approach, 501
Homocysteine Metabolism488 Gender
and Genetics488 Lifestyle489
Homocysteine is an intermediate in the conversion of the amino acid methionine to cysteine. Elevated homocysteine levels are an independent risk factor for coronary heart disease, stroke, and other vascular conditions. Homocysteine and its relation-ship to cardiovascular disease emerged in the late 1960s, when Kilmer McCully, MD encountered two children with homocystinuria (a rare autosomal recessive condi-tion) who had advanced atherosclerosis, although the coronary plaques contained no lipids. Increased homocysteine levels have been implicated in several other clinical conditions, including neural tube defects, spontaneous abortion, placental abrup-tion, renal failure, noninsulin-dependent diabetes and complications of diabetes, rheumatoid arthritis, alcoholism, osteoporosis, and neuropsychiatric disorders.
同型半胱氨酸是氨基酸甲硫氨酸转化为半胱氨酸的中间体。 升高的同型半胱氨酸水平是冠心病,中风和其他血管疾病的独立危险因素。 同型半胱氨酸及其与心血管疾病的关系出现在20世纪60年代后期,当时Kilmer McCully医学博士遇到两名儿童患有高胱氨酸尿症(一种罕见的常染色体隐性疾病)患有晚期动脉粥样硬化,尽管冠状动脉斑块不含脂质。 同型半胱氨酸水平的升高也与其他一些临床疾病有关, 包括神经管缺陷,自然流产,胎盘早剥,肾衰竭,非胰岛素依赖性糖尿病和糖尿病并发症,类风湿性关节炎,酒精中毒,骨质疏松症和神经精神病症。
Homocysteine is metabolized along two pathways: remethylation to methionine(which requires methionine synthase along with vitamin B12 and folic acid or betaine) or transsulfuration to cysteine (which requires vitamin B6). A defect in either of these pathways leads to accumulation of homocysteine. Insufficient dietary intake of vitamin B6, vitamin B12, and folic acid can lead to increased homocysteine levels.
型半胱氨酸通过两种途径代谢:甲基化还原为蛋氨酸(需要蛋氨酸合成酶以及维生素B12和叶酸或甜菜碱)或转化为半胱氨酸 (需要维生素B6)。 这些途径中的任何一个缺陷都会导致同型半胱氨酸的积累。 膳食摄入维生素B6, 维生素B12和叶酸不足会导致同型半胱氨酸水平升高。
Gender and Genetics 性别与遗传
Studies of healthy men and women indicate that certain acquired and genetic deter-minants may affect total plasma homocysteine. Women tend to have lower basal levels than men,1 and neither contraceptives nor hormone replacement therapy seem to alter their levels significantly.2 However, in postmenopausal women, hor-mone replacement therapy might slightly decrease elevated homocysteine concen-trations. No significant lowering effect was observed in women with low homocysteine levels.3 Generally, homocysteine concentrations are significantly higher in postmenopausal women than in premenopausal women; however, the previously mentioned sex differences in homocysteine concentrations persist even in elderly populations.4-6 The antiestrogen drug tamoxifen, used in the long-term treatment of breast cancer patients, was reported to decrease homocysteine levels in postmenopausal women with breast cancer.7
对健康男性和女性的研究表明,某些获得性遗传因素可能影响总血浆同型半胱氨酸。 女性的基础水平往往低于男性1,避孕药和激素替代疗法似乎都没有显着改变其水平。 2然而,在绝经后的女性中,激素替代疗法可能会略微降低同型半胱氨酸浓度的升高。 同型半胱氨酸水平低的女性没有观察到明显的降低效果。3一般来说,绝经后女性的同 型半胱氨酸浓度显着高于绝经前女性; 然而,前面 到的同型半胱氨酸浓度的性别差异在老年人群中仍然存在。4-6据报道,用于乳腺癌患者长期治疗的抗雌激素药物他莫昔芬可降低绝经后乳腺癌患者的同型半胱氨酸水平 。 TF471
A number of reports also demonstrated that elevated plasma total homocysteine in children was correlated to either cardiovascular disease or death in their parents or close relatives. This relationship was observed in both white and black children, and in white children with hypercholesterolemia. In the latter study group, the 5,10-methylenetetrahydrofolate reductase (MTHFR) TT genotype tended to be most frequent in children with a parental history of cardiac disease.8 Epidemiologic evidence showed homocysteine levels to be more than 45% lower in Westernized adult black Africans than in age-matched white adults, revealing racial genetic dif-ferences in homocysteine metabolism.9
许多报告还表明,儿童血浆总同型半胱氨酸升高与其父母或近亲的心血管疾病或死亡相关。 在白人和黑人儿童以及患有高胆固醇血症的白人儿童中观察到这种关系。 在后一研究组中,5,10-亚甲基四氢叶酸还原酶 (MTHFRTT基因型在患有父母心脏病史的儿童中最常见。8流行病学证据显示西方化的同型半胱氨酸水平低于45%成年黑人非洲人比年龄相匹配的白人成年人,揭示了同型半胱氨酸代谢中的种族遗传差异。9
The MTHFR gene has two different alleles where the Tallele is associated with decreased enzyme activity, hyperhomocysteinemia, and increased risk for thrombo-embolism in coronary heart disease. The presence of the Callele is correlated to lower homocysteine levels and, not surprisingly, may even provide protection against occlusion of coronary arteries. One Hungarian study concluded that the carriers of the T allele with coronary heart disease died earlier due  to myocardial infarction.10
MTHFR基因具有两个不同的等位基因,其中“T” 等位基因与降低的酶活性,高同型半胱氨酸血症和冠心病中血栓栓塞的风险增加相关。  “C”等位基因的存在与同型半胱氨酸水平降低有关,甚至可以提供保护,以防止冠状动脉阻塞。匈牙利的一项研究得出结论,携带冠心病T等位基因的人因心肌梗死而提前死亡。10
Lifestyle 生活方式
An association between coffee and black tea consumption and the concentration of total homocysteine in plasma has been reported.11 A marked positive doseresponse relation between coffee con-sumption and plasma homocysteine levels was observed. The rela-tionship was most marked in males and females consuming more than eight cups of coffee per day. The combination of cigarette smoking and high coffee intake was associated with particularly high homocysteine concentrations.12 Long-term ingestion of alco-hol has also been associated with increased homocysteine lev-els.13,14 Plasma total homocysteine is inversely related to exercise.15
已经报道了咖啡和红茶消费之间的关联以及血浆中总同型半胱氨 酸的浓度。11观察到咖啡消耗和血浆同型半胱氨酸水平之间显着 的正剂量 - 反应关系。 这种关系在男性和女性中最为明显,每天消费超过8杯咖啡。 吸烟与高咖啡摄入量的结合与特别高的同 型半胱氨酸浓度有关。12长期摄入酒精也与同型半胱氨酸水平升 高有关。13,14血浆总同型半胱氨酸与运动呈负相关。15
Nutritional Relationships 营养关系
Nutrition affects homocysteine concentrations in both men and women. For example, individuals in the lowest quartiles for serum folate and vitamin B12 have significantly higher concentrations of homocysteine, and men in the lowest quartile of serum pyridoxal 5-phosphate (P5P; the bioactive form of vitamin B6) also have increased homocysteine concentrations.2
营养会影响男性和女性的同型半胱氨酸浓度。 例如,血清叶酸 和维生素B12最低四分位数的个体具有显着更高的同型半胱氨酸浓 度,而血清吡哆醛5'-磷酸(P5P;生物活性形式的维生素B6)的 最低四分位数的男性同型半胱氨酸浓度也增加。2
Methionine 蛋氨酸
Metabolism of the amino acid methionine, a limiting amino acid in the synthesis of many proteins, affects several biochemical pathways involving the production of nutrients that are essential to the optimal functioning of the cardiovascular, skeletal, and nervous system.
Homocysteine is an intermediate product of methionine metabolism and is metabolized by two pathways: the remethyl-ation pathway, which regenerates methionine, and the trans-sulfuration pathway, which degrades homocysteine into cysteine and then taurine. In essence, the intermediate metabolite homocysteine is located at a metabolic crossroads, so it directly and indirectly affects all methyl and sulfur group metabolism occurring in the body. Experiments demonstrated that high lev-els of l-homocysteine and adenosine in the cell inhibit all methylation reactions.16
同型半胱氨酸是甲硫氨酸代谢的中间产物,并且通过两种途径代谢:再甲基化途径,其再生蛋氨酸;和转硫途径,其将同型半胱氨酸降解为半胱氨酸然后牛磺酸。 实质上,中间代谢物高半胱氨酸位于代谢的十字路口,因此它直接和间接地影响体内发生的所有甲基和硫基代谢。 实验证明,细胞中高水平的:L-高半胱氨酸和腺苷抑制所有甲基化反应。16
The remethylation pathway (Figure 54-1) comprises two inter-secting biochemical pathways and results in the transfer of a methyl group (CH3) to homocysteine by either methylcobalamin or beta-ine (trimethylglycine). Methylcobalamin originally receives its methyl group from S-adenosylmethionine (SAMe) or 5-methyltetrahydrofolate (5-methylTHF), an active form of folic acid. After remethylation, methionine can be reused to produce SAMe, the bodys universal methyl donor,which participates in several key metabolic pathways, including methylation of DNA and myelin, synthesis of carnitine, coenzyme Q10 (CoQ10), creatine, epinephrine, melatonin, methylcobalamin, and phosphatidylcho-line (PC), as well as phase 2 methylation detoxification reactions.
再甲基化途径(图54-1)包含两个相交的生化途径,并导致甲钴胺(MecobalaminB12  methylcobalamin 或甜菜碱(三甲基甘氨酸)将甲基(CH3)转移至高半胱氨酸。 甲钴胺最初从S-腺苷甲硫氨酸(SAMe)或5-甲基四氢叶酸(5-甲基THF)(叶酸的活性形式)接收甲基。 重新甲基化后,蛋氨酸可以重新用于生产身体的“通用甲基供体”SAMe,它参与了几个关键的代谢途径,包括DNA和髓鞘的甲基化,肉碱的合成,辅酶Q10CoQ10),肌酸,肾上腺素,褪黑激素,甲基钴胺素和磷脂酰胆碱(PC),以及肝脏2期解毒过程的甲基化反应。
The transsulfuration pathway of methionine/homocysteine degradation (see Figure 54-1) produces the amino acids cysteine and taurine, which are important nutrients for cardiac health, hepatic detoxification, cholesterol excretion, bile salts formation, and glutathione (GSH) production. This pathway depends on
甲硫氨酸/高半胱氨酸的转硫途径降解(见图54-1)产生氨基酸半胱氨酸和牛磺酸,它们是心脏健康,肝脏解毒,胆固醇排泄,胆汁盐形成和谷胱甘肽(GSH)产生的重要营养素。 这条路依赖于
FIGURE 54-1 Homocysteine metabolism. DMG, dimethylglycine; 5-methylTHF, 5-methyltetrahydrofolate; P5P, pyri-doxal 5-phosphate (vitamin B6); SAH, S-adenosylhomocysteine; SAMe, S-adenosylmethionine; THF, tetrahydrofolate.adequate
54-1同型半胱氨酸代谢。  DMG,二甲基甘氨酸;  5-甲基THF5-甲基四氢叶酸;  P5P,吡哆醛5'-磷酸(维生素B6;SAHS-腺苷高半胱氨酸;  SAMeS-腺苷甲硫氨酸;  THF,四氢叶酸。
dietary intake and hepatic conversion of vitamin B6 into its active form, P5P. The amino acid serine, a down-line metabo-lite generated from betaine via the homocysteine remethylation pathway, is also necessary.In addition to 5-methylTHF, methylcobalamin, betaine, and P5P, N-acetylcysteine (NAC) has been reported to significantly lower homocysteine levels.17
足够的膳食摄入量和肝脏将维生素B6转化为活性形式P5P。 氨基酸丝氨酸是通过高半胱氨酸重甲基化途径从甜菜碱产生的下线代谢物,也是必需的。据报道,除了5-甲基四氢叶酸,甲基钴胺素,甜菜碱和P5P以外,N-乙酰半胱氨酸(NAC)也可显着降低高半胱氨酸水平。17
S-Adenosylhomocysteine  S-腺苷甲硫氨酸
The metabolic precursor of homocysteine in all tissues is S-adenosylhomocysteine, which is more difficult to measure than homocysteine, but has recently been indicated as a more sensitive marker for cardiovascular disease and Alzheimers disease. S-adenosylhomocysteine is formed by the demethylation of SAMe (Figure  54-2). S-adenosylhomocysteine hydrolase catalyzes the hydrolysis of S-adenosylhomocysteine to adenosine and homocys-teine. S-adenosylhomocysteine hydrolase deficiency is a genetic disorder of methionine metabolism that results in slow psychomo-tor development.
Increased levels of S-adenosylhomocysteine may occur when the intracellular concentration of homocysteine increases.18-20
所有组织中同型半胱氨酸的代谢前体是 S-腺苷甲硫氨酸 Sadenosylhomocysteine,它比同型半胱氨酸更难测量,但最近 S-腺苷甲硫氨酸 已被证明是心血管疾病和阿尔茨海默病的更敏感的标志物。 通过SAMe的去甲基化形成S-腺苷高半胱氨酸(图54-2)。 S-腺苷高半胱氨酸水解酶催化S-腺苷高半胱氨酸水解成腺苷和高半胱氨酸。  S-腺苷高半胱氨酸水解酶缺乏症是蛋氨酸代谢的遗传疾病,其导致精神运动发育缓慢。当同型半胱氨酸的细胞内浓度增加时,可能会出现S-腺苷同型半胱氨酸水平升高的情况。18-20
Methyltetrahydrofolate 甲基四氢叶酸
Folates function as carbon donors in the synthesis of serine from glycine, directly in the synthesis of purines and pyrimidine bases, and indirectly in the synthesis of transfer RNA. Folates also func-tion as methyl donors to create methylcobalamin, which is used for remethylation of homocysteine to methionine. Dietary folic acid is a mixture of folates in the form of polyglutamates, which are readily destroyed by cooking.
叶酸在甘氨酸合成丝氨酸中起直接作用,在嘌呤和嘧啶碱的合成中起到碳供体的作用,间接在转移RNA的合成中起作用。 叶酸还起甲基供体的作用,以产生使用的甲钴胺用于将高半胱氨酸重新甲基化为甲硫氨酸。 膳食叶酸是多谷氨酸盐形式的叶酸混合物,其易于通过烹饪破坏。
Synthesis of the active forms of folic acid is a complex process requiring several enzymes, as well as adequate supplies of niacin, P5P, and serine as cofactors (Figure 54-3). In plants, folic acid is formed from a hetero-bicyclic pteridine ring, para-aminobenzoic acid, and glutamic acid. Folate is initially deconjugated in the cells of the intestinal wall to the monoglutamate form. This is then reduced to dihydrofolate and then to tetrahydrofolate (THF) via folate and dihydrofolate reductase. Both enzymes require reduced nicotinamide adenine dinucleotide phosphate (niacin dependent) as a cofactor. Serine combines with P5P to transfer a hydroxy-methyl group to THF. This results in the formation of 5,10-methylenetetrahydrofolate (5,10-methyleneTHF) and gly-cine. This molecule is of central importance, being the precursor of the metabolically active 5-methylTHF, which is involved in homo-cysteine metabolism, and 10-formyltetrahydrofolate (involved in purine synthesis), as well as functioning on its own in the genera-tion of thymine side chains for incorporation into DNA.
活性形式的叶酸的合成是一个复杂的过程,需要几种酶,以及烟酸,P5P和丝氨酸作为辅助因子的充足供应(图54-3)。 在植物中,叶酸由杂双环蝶啶环,对氨基苯甲酸和谷氨酸形成。 叶酸最初在肠壁细胞中解偶联成单谷氨酸形式。 然后将其还原为二氢叶酸,然后通过叶酸和二氢叶酸还原酶还原为四氢叶酸 (THF)。 两种酶都需要还原的烟酰胺腺嘌呤二核苷酸磷酸盐 (烟酸依赖性)作为辅助因子。 丝氨酸与P5P结合以将羟甲基转移至THF。 这导致形成5,10-亚甲基四氢叶酸(5,10-亚甲基THF)和甘氨酸。 该分子具有重要意义,是代谢活性5-甲基THF(参与同型半胱氨酸代谢)和10-甲酰基四氢叶酸(参与嘌呤合成)的前体,以及在胸腺嘧啶侧链产生中发挥作用。用于掺入DNA
The following may contribute to a deficiency of folic acid:
A deficient food supply
A defect in utilization, as in alcoholics
Increased needs in pregnant women and cancer patients
Metabolic interference by drugs
Folate losses in hemodialysis
• 食物供应不足
• 利用方面的缺陷,如酗酒者
• 吸收不良
• 孕妇和癌症患者的需求增加
• 药物代谢干扰
• 血液透析中的叶酸损失
FIGURE 54-2 Methionine, AdoMet (S-adenosylmethionine), and AdoHcy metabolism. (From Baric I, Fumić K, Glenn B, et al. S-adenosylhomocysteine hydrolase deciency in a human: a genetic disorder of methionine metabolism. Proc Natl Acad Sci , 2004:101:4234-4239.)
54-2蛋氨酸,AdoMetS-腺苷甲硫氨酸)和AdoHcy代谢。  (来自Baric IFumićKGlenn Bet al.S-
adenosylhomocysteine hydrolase deciency in a humana genetic disorder of methionine metabolism.Proc Natl Acad Sci20041014234-4239。)
FIGURE 54-3 Absorption and activation of folic acid. DHF, dihydrofolate; 5,10-METHF, 5,10-methylenetetrahydrofolate; 5-MTHF, 5-methyltetrahydrofolate; MTHFR, methylenetetrahydrofolate reductase; P5-P, pyridoxal 5-phosphate; R5-P, riboavin 5-phosphate; THF, tetrahydrofolate.
54-3叶酸的吸收和活化。  DHF,二氢叶酸;  5,10-METHF5,10-亚甲基四氢叶酸;  5-MTHF5-甲基四氢叶酸; MTHFR,亚甲基四氢叶酸还原酶;  P5'-P,吡哆醛5'-磷酸;  R5'-P,核糖核苷5'-磷酸;  THF,四氢叶酸。
Enzyme or cofactor deficiency necessary for generation of active folic acid Individuals using supplements or consuming either breakfast cereals or green leafy vegetables have significantly greater plasma folate and lower homocysteine levels than those who do not.1
• 生成活性叶酸所必需的酶或辅因子缺乏症的个体在使用补充剂或食用早餐谷类食品或绿叶蔬菜后,其血浆叶酸含量显着高于同类药物,而同型半胱氨酸水平低于那些没有使用这些方式的个体。1
Folinic acid (5-formylTHF), available supplementally as cal-cium folinate (also known as leucovorin calcium), is an immediate precursor to 5,10-methyleneTHF and 5-methylTHF. Folinic acid can correct deficiencies of the active forms of folic acid, is more stable than folic acid, and has a longer half-life in the body. Folinic acid also readily crosses the bloodbrain barrier and is slowly cleared, compared with folic acid, which is poorly transported into the brain and, once in the central nervous system (CNS), is rapidly cleared.21
作为亚叶酸钙(也称为亚叶酸钙)补充的亚叶酸(5-甲酰基THF)是5,10-亚甲基-THF5-甲基-THF的直接前体。 亚叶酸可以纠正活性形式叶酸的缺乏,比叶酸更稳定,并且在体内具有更长的半衰期。 与叶酸相比,亚叶酸也很容易穿过血脑屏障并慢慢清除,而叶酸很难进入大脑,一旦进入中枢神经系统(CNS), 就会迅速清除。21
Methylcobalamin 甲钴胺
The coenzyme form of vitamin B12 is a complex molecule containing cobalt bound to five nitrogens and one carbon. The metalcarbon bond found on this coenzyme is the only known biological example of this type of linkage. The use of cobalt in the two biologically active forms of cobalamin, adenosylcobalamin and methylcobalamin, is the only known function of this metal in biological systems.
辅酶形式的维生素B12是一种复杂的分子,含有与五个氮和一个碳结合的钴。 在该辅酶上发现的金属 - 碳键是这种类型连接的唯 一已知生物学实例。 钴在钴胺素,腺苷钴胺素和甲基钴胺素的两种生物活性形式中的使用是该金属在生物系统中唯一已知的功能。
In humans, the cobalt in cobalamin exists in a univalent oxida-tion state, designated as cob(I)alamin. The compound commonly referred to as vitamin B12 has a cyanide molecule at the metalcarbon position, and the oxidation state of the cobalt is +3 instead of the biologically active +1. To be used in the body, the cyanide molecule must be removed. It is thought that the compound GSH may perform this function. Other available forms of vitamin B12 include hydroxocobalamin and the two active forms, adenosylco-balamin (cobamamide) and methylcobalamin.
在人类中,钴胺素中的钴以单价氧化态存在,称为cobIalamin。 通常称为维生素B12的化合物在金属碳位置具有氰化物分子,并且钴的氧化态为+3而不是生物活性+1。 要在体内使用,必须除去氰化物分子。 认为化合物GSH可以执行该功能。 其他可用形式的维生素B12包括羟钴胺素hydroxocobalamin 和两种活性形式,腺苷钴胺素 adenosylco-balamincobamamide)和甲基钴胺素。
The absorption of dietary cobalamin requires the formation of a complex between dietary vitamin B12 and R-proteins and the secretion, by the stomach mucosa, of intrinsic factor. The vitamin B12 complex is split by pancreatic proteases, and the released vita-min B12 attaches to intrinsic factor and is absorbed in the distal ileum. The amount of cobalamin required in the diet is low, and even people with pernicious anemia can generally absorb sufficient amounts if the coenzyme is supplemented at a high enough dosage.
膳食维生素B12的吸收需要在膳食维生素B12R-蛋白质之间形成复合物,并且通过胃粘膜分泌内在因子。 维生素B12复合物被胰蛋白酶分裂,释放的维生素B12附着于内在因子并被回肠末端吸收。 饮食中所需的钴胺素的量很低,如果以足够高的剂量补充辅酶,即使患有恶性贫血的人也可以吸收足够的量。
Although the basic cobalamin molecule is only synthesized by microorganisms, all mammalian cells can convert this into the coenzymes adenosylcobalamin and methylcobalamin. Adeno-sylcobalamin is the major form in cellular tissues, where it is retained in the mitochondria. Methylcobalamin predominates in blood plasma and certain other body fluids, and in cells found in the cytosol.
尽管碱性钴胺素分子仅由微生物合成,但所有哺乳动物细胞都可将其转化为辅酶腺苷钴胺素和甲钴胺素。 腺苷钴胺是细胞组织中的主要形式,其保留在线粒体中。 甲钴胺在血浆和某些其他体液以及细胞质中发现的细胞中占主导地位。
Adenosylcobalamin functions in reactions in which hydrogen groups and organic groups exchange places. In humans, adenosyl-cobalamin is required in only two reactions: the catabolic isomeri-zation of methylmalonyl coenzyme A (CoA) to succinyl CoA and interconversion of α- and β-leucine. After its formation from methylmalonyl CoA, succinyl CoA is either involved in the syn-thesis of porphyrin molecules (along with glycine) or it transfers its CoA to form acetyl CoA. The latter reaction is magnesium dependent, and the remaining succinate is fed into the citric acid cycle. Deficiencies in this coenzyme form of vitamin B12 result in increased amounts of methylmalonyl CoA and generally an increase in glycine levels.
腺苷钴胺在氢基团和有机基团交换位置的反应中起作用。 在人类中,仅在两个反应中需要腺苷钴胺素:甲基丙二酰辅酶A CoA)向琥珀酰CoA的分解代谢异构化和α-和β-亮氨酸的相互转化。 在由甲基丙二酰基CoA形成后,琥珀酰CoA参与卟啉分子的合成(与甘氨酸一起)或其转移其CoA以形成乙酰CoA。 后一 反应是镁依赖性的,剩余的琥珀酸盐进料到柠檬酸循环中。 这种辅酶形式的维生素B12的缺乏导致甲基丙二酰辅酶A的量增加, 并且通常甘氨酸水平增加。
Methylcobalamins only known biological function in humans is in the remethylation of homocysteine to methionine via the enzyme methionine synthase, also known as 5-methyltetrahydrofolate-homocysteine methyltransferase. To originally form methylcobala-min from cyanocobalamin or other Cob(III)alamin or Cob(II)ala-min precursors, SAMe must be available to supply a methyl group. Once methylcobalamin is formed, it functions in the regeneration of methionine by transferring its methyl group to homocysteine. Methyl-cobalamin can then be regenerated by 5-methylTHF (Fig-ure 54-4). The cells ability to methylate important compounds such as proteins, lipids, and myelin is compromised by a deficiency of either folate or vitamin B12.22 Shortages of active folic acid, SAMe, or a dietary deficiency of cobalamin lead to a decrease in the generation of methylcobalamin and a subsequent impairment of homocysteine metabolism. Because lack of methylcobalamin leads to depressed DNA synthesis, rapidly dividing cells in the brain and elsewhere are affected.
甲钴胺是人类唯一已知的生物学功能是通过甲硫氨酸合成酶将同型半胱氨酸再甲基化为甲硫氨酸,也称为5-甲基四氢叶酸 - 高半胱氨酸甲基转移酶。 为了最初从氰钴胺素或 其他CobIIIalaminCobIIalamin前体形成甲钴胺,SAMe必须可用于提供甲基。 一旦甲钴胺形成,它通过将甲基转移至高半胱氨酸而在甲硫氨酸的再生中起作用。 然后甲基钴胺素可以通过5-甲基THF再生(图54-4)。 细胞对蛋白质,脂类和髓磷脂等重要化合物进行甲基化的能力受到叶酸或维生素B12缺乏的影响。22 活性叶酸, SAMe缺乏或维生素B不足导致甲钴胺的产生减少和随后的高半胱氨酸代谢受损。 由于甲基钴胺素的缺乏导致DNA合成减少,因此大脑和其他地方的快速分裂细胞受到影响。
At least 12 different inherited inborn errors of metabolism related to cobalamin are known. Abnormalities are detectable by urine and plasma assays of methylmalonic acid and homocysteine; and plasma and erythrocyte analysis of cobalamin coenzymes, which can reveal deficiencies of methylcobalamin or adenosylcobalamin.23
已知至少12种与钴胺素相关的遗传性先天性代谢缺陷。 甲基丙二酸和高半胱氨酸的尿液和血浆检测可检测到异常; 和等离子,钴胺素辅酶的红细胞和红细胞分析,可以揭示甲钴胺或腺苷钴胺的缺陷。23
FIGURE 54-4 Cobalamin metabolism. 54-4钴胺素代谢。
Betaine 甜菜碱
The metabolic pathways of betaine, methionine, methylcobala-min, and methylTHF are interrelated, intersecting at the regen-eration of methionine from homocysteine. This regeneration is accomplished in one of two ways. One involves the generation in the cytosol of 5-methylTHF from methylene THF and the trans-fer of its methyl group to regenerate methylcobalamin, which then acts as a coenzyme in the regeneration of methionine. Because THF and its derivatives can only cross the mitochondrial mem-brane slowly, inside, the mitochondria regeneration of methionine relies on recovery of a methyl group from betaine.
甜菜碱,甲硫氨酸,甲基钴胺素和甲基THF的代谢途径是相互关联的,在同型半胱氨酸的甲硫氨酸再生时相交。 这种再生以两种方式之一完成。 一种方法涉及从亚甲基THF中在细胞溶胶中产生5-甲基THF,并将其甲基转移至再生甲基钴胺素,然后甲钴胺再生甲硫氨酸作为辅酶。 因为THF及其衍生物只能在内部缓慢穿过线粒体膜,所以蛋氨酸的线粒体再生依赖于从甜菜碱中回收甲基。
Betaine donates one of its three methyl groups via the enzyme betaine-homocysteine methyltransferase to homocysteine, result-ing in the regeneration of methionine. After the donation of the methyl group, one molecule of dimethylglycine remains. This molecule is oxidized to glycine and to two molecules of formalde-hyde by riboflavin-dependent enzymes. The formaldehyde can combine with THF within the mitochondria to generate one of the active forms of folic acid, methylenetetrahydrofolate, which can be converted to 5-methylTHF and subsequently used as a methyl donor (Figure 54-5).
甜菜碱通过酶甜菜碱 - 高半胱氨酸甲基转移酶将其三个甲基之一捐赠给高半胱氨酸,导致甲硫氨酸的再生。 捐赠甲基后, 剩下一分子二甲基甘氨酸。 该分子被核黄素依赖性酶氧化成甘氨酸和两分子甲醛。 甲醛可与线粒体内的THF结合,生成叶酸, 亚甲基四氢叶酸的活性形式之一,可转化为5-甲基THF,随后用 作甲基供体(图54-5)。
In animal studies, a disturbance in the metabolism of either of the two methyl-donor pathways, due to limited availability of either betaine or folates and vitamin B12, affects levels of nutrients in the coexisting pathway, because more of a drain is placed on the other pathway as a source of methyl groups. Rats fed diets defi-cient in choline and methionine had hepatic folate concentrations half that of controls after 5 weeks.24 During choline deficiency, hepatic SAMe concentrations were also shown to decrease by as much as 50%.25 Similarly, THF deficiency resulted in decreased hepatic total choline levels.26
Patients with a congenital deficiency of the enzyme MTHFR, which is needed for the formation of 5-methylTHF, have reduced levels of both methionine and SAMe in the cerebrospinal fluid and show demyelination in the brain and degeneration of the spi-nal cord. Methionine is effective in the treatment of some of these patients; however, betaine was shown to restore cerebrospinal fluid SAMe levels to normal and to prevent the progress of neurologic symptoms in all patients in whom it was tried.27
在动物研究中,由于甜菜碱或叶酸和维生素B12的有限可用性, 两种甲基供体途径中的任一种的代谢紊乱影响共存途径中的营养物水平,因为更多的排泄物是作为甲基的来源放置在另一个途径 上。 喂食缺乏胆碱和蛋氨酸的饮食的大鼠在5周后肝脏叶酸盐浓度是对照组的一半。24在胆碱缺乏期间,肝脏SAMe浓度也显示降低多达50%。25同样,THF缺乏导致降低肝脏总胆碱水平。26具有先天性缺乏MTHFR酶的患者,其形成5-甲基-THF,脑脊液中甲硫氨酸和SAMe水平均降低并显示大脑中的脱髓鞘和脊髓的退化。 蛋氨酸可有效治疗其中一些患者; 然而,甜菜碱被证明能够使脑脊液SAMe水平恢复正常, 并防止所有患者的神经系统症状进展。27
FIGURE 54-5 Phosphatidylcholine metabolism. 54-5磷脂酰胆碱代谢。
FIGURE 54-6 Synthesis of taurine. 54-6牛磺酸的合成。
Betaine supplementation has been shown to reduce homocyste-ine levels28 while resulting in modest increases of plasma serine and cysteine levels.29 Stimulation of betaine-dependent homocys-teine remethylation causes a commensurate decrease in plasma homocysteine that can be maintained as long as supplemental betaine is taken.30
Serine levels are depressed in some individuals with excess homocysteine who are treated with folic acid, cobalamin, and vita-min B6.31 Because serine is required (1) for the conversion of folic acid to its active form, (2) as a shuttle for methyl groups between the cytosol and the mitochondria, and (3) as a cofactor in the transsulfuration pathway of methionine/homocysteine metabo-lism, supplementation with betaine should be included with folic acid, cobalamin, and P5P to optimize the interrelated pathways of homocysteine metabolism.
一些患有同型半胱氨酸水平过量的患者通过补充叶酸,维生素B和维生素B6的治疗而丝氨酸水平下降。31因为叶酸转化为活性形式需要丝氨酸 (1),(2)作为细胞质和线粒体之间的甲基基团的穿梭,和 (3)作为甲硫氨酸/高半胱氨酸代谢的转硫途径中的辅助因子, 叶酸,钴胺素和P5P中应包含甜菜碱的补充,以优化相互关联的途径。同型半胱氨酸代谢。
Pyridoxal 5-Phosphate 吡哆醛5'-磷酸盐
P5P is the active coenzyme form of vitamin B6. This cofactor is involved in myriad biological processes, including the transsul-furation pathway of homocysteine. This degradation pathway involves a two-step process, resulting in the formation of cysta-thionine and its subsequent cleavage to cysteine. Cystathionine synthase and cystathioninase require P5P as a cofactor, and the committed first step in the degradation of homocysteine, cysta-thionine synthase, also requires serine, a downstream metabolite of betaine (Figure 54-6). Some studies suggest that cystathio-nine could be a useful marker to assess the effect of vitamin B6 and should be monitored with homocysteine to better elucidate clinical outcomes.32
P5P是维生素B6的活性辅酶形式。 该辅因子参与无数生物过程, 包括同型半胱氨酸的转硫途径。 该降解途径涉及两步过程, 导致胱硫醚的形成及其随后的半胱氨酸切割。 胱硫醚合酶和胱硫醚酶需要P5P作为辅助因子,降解同型半胱氨酸,胱硫醚合成酶的第一步,也需要丝氨酸,甜菜碱的下游代谢产物 (图54-6)。 一些研究表明,胱硫醚可能是评估维生素B6作用的有用标志物,应该用同型半胱氨酸监测,以更好地阐明临床结果。32
Once cysteine is generated, it can be directed into several differ-ent pathways, including synthesis of GSH, acetyl CoA, and taurine. Three pathways from cysteine to taurine are known; all require P5P.
一旦产生半胱氨酸,它可以被导入几种不同的途径,包括GSH, 乙酰辅酶A和牛磺酸的合成。 从半胱氨酸到牛磺酸的三种途径是 已知的; 都需要P5P
Impaired kidney function appears to be a factor in raised homo-cysteine concentrations.33 It has been shown that a decreased glomerular filtration rate may be a contributing factor, and some researchers suggest that hyperhomocysteinemia may actually reflect early nephrosclerosis,8 although other studies demon-strate only a minor renal influence.34 Fenofibrate treatment, known to increase homocysteine levels, is also known to pro-mote elevations in serum creatinine (see Pharmaceutic Drug Effects on Homocysteine).35 Cystatin C, a creatinine-indepen-dent indicator of glomerular filtration rate, has also been shown to be well associated with homocysteine levels in kidney trans-plantation patients, as well as those with coronary disease.35,36
肾功能受损似乎是同型半胱氨酸浓度升高的一个因素。33已经显示出降低了肾小球滤过率可能是一个促成因素,一些研究人员认为高同型半胱氨酸血症实际上可能反映早期肾硬化8,尽管其他研究表明只有轻微的肾脏影响。34非诺贝特治疗,已知能提高同型半胱氨酸水平,血清肌酐升高也是众所周知的。(参见“药物药物对同型半胱氨酸的影响”)。35胱抑素C是一种不依赖肌酐的肾小球滤过率指标,也被证明与肾移植患者的同型半胱氨酸水平密切相关。作为冠心病 患者。35,36
Fibrates such as gemfibrozil are a class of drugs used to lower tri-glycerides and raise high-density lipoprotein levels. In a paradoxic effect working against a safer cardiac risk profile, these drugs have been observed to raise homocysteine levels up to 40%.35,37,38 The mechanism of this observation is unknown, although it seems that renal mechanisms may be involved (see Renal Function).
吉非贝齐等贝特类药物是一类用于降低甘油三酯和提高高密度脂蛋白水平的药物。 在对抗更安全的心脏风险特征的矛盾效应中, 已经观察到这些药物将同型半胱氨酸水平提高至40%。35,37,38这 种观察的机制尚不清楚,尽管似乎可能涉及肾脏机制(参见“肾 脏”)功能”)。
Thiazides and angiotensin-converting enzyme inhibitors are often a first-line conventional treatment to lower elevated blood pressure. One preliminary, randomized, prospective treatment study investigated 40 hypertensive patients after treatment with hydrochlorothiazide or captopril. In this study vitamins B6, B12, folic acid, creatinine, and cystatin C were used as parame-ters of renal function. For 31 and 29 days, respectively, 21 patients were prescribed hydrochlorothiazide and 19 were pre-scribed captopril. It was found that hydrochlorothiazide, but not captopril, significantly raised homocysteine by 16%, as well creatinine and cystatin C.39
噻嗪类和血管紧张素转换酶抑制剂通常是降低血压升高的一线常规治疗方法。 一项初步的,随机,前瞻性治疗研究调查了用 氢氯噻嗪或卡托普利治疗后的40名高血压患者。 在该研究中, 维生素B6B12,叶酸,肌酸酐和胱抑素C被用作肾功能的参数。 分别为31天和29天,21例患者服用氢氯噻嗪,19例服用卡托普利。结果发现氢氯噻嗪而非卡托普利显着提高了16%的同型半胱氨酸, 以及肌酐和胱抑素C.39
Because of its central role in sulfur and methyl group metabolism,elevated levels of homocysteine would be expected to negatively affect the biosynthesis of all of the following: SAMe, carnitine, chondroitin sulfates, CoA, CoQ10, creatine, cysteine, dimethylg-lycine, epinephrine, glucosamine sulfate, GSH, glycine, melato-nin, pantethine, phosphatidylcholine, phosphatidylserine, serine, and taurine.
由于其在硫和甲基代谢中的核心作用,高半胱氨酸水平预计会对以下所有物质的生物合成产生负面影响:SAMe,肉毒碱,硫酸软骨素,CoACoQ10,肌酸,半胱氨酸,二甲基甘氨酸,肾上腺素,硫酸氨基葡萄糖,谷胱甘肽,甘氨酸,褪黑激素,泛硫乙胺,磷 脂酰胆碱,磷脂酰丝氨酸,丝氨酸和牛磺酸。
S-Adenosylmethionine S-腺苷甲硫氨酸
SAMe is formed by the transfer of an adenosyl group from ade-nosine triphosphate to the sulfur atom of methionine. This reac-tion requires magnesium as a cofactor. When methyl groups are transferred from SAMe, S-adenosylhomocysteine is formed. This is then hydrolyzed to release the adenosine and results in the formation of homocysteine.
通过将腺苷三磷酸的腺苷转移至蛋氨酸的硫原子形成SAMe。 该反应需要镁作为辅助因子。 当甲基从SAMe转移时,形成S-腺苷高半胱氨酸。 然后将其水解以释放腺苷并导致高半胱氨酸的形成。
SAMe is known to be used in the synthesis of the following compounds: carnitine, CoQ10, creatine, methylcobalamin from cob(III)alamin, 1-methylnicotinamide, N-methyltryptamine, PC, and polyamines. It is also used in methylation reactions as part of hepatic phase 2 detoxification.
已知SAMe用于合成以下化合物:肉毒碱,CoQ10,肌酸,来 自穗轴(III)氨基的甲基钴胺素,1-甲基烟酰胺,N-甲基色 胺,PC和多胺。 它也用于甲基化反应,作为肝脏2期解毒的 一部分。
Carnitine 左旋肉碱
A trimethylated amino acid roughly similar in structure to choline, carnitine is a cofactor for transformation of free long-chain fatty acids into acyl-carnitines and their transport into a mitochondrial matrix, where they undergo β-oxidation for cellular energy pro-duction. Synthesis of carnitine begins with the methylation of the amino acid l-lysine by SAMe. Methionine, magnesium, vitamin C, iron, P5P, and niacin, along with the cofactors responsible for regenerating SAMe from homocysteine (5-methylTHF, methylco-balamin, and betaine), are required for optimal carnitine synthesis (Figure 54-7).
卡尼汀是一种结构与胆碱大致相似的三甲基化氨基酸,是游离长链脂肪酸转化为酰基肉碱及其转运的辅助因子,然后,它们被转运到线粒体基质中,在那里,它们经过β氧化产生细胞能量.肉毒碱的合成始于甲基化SAMel-赖氨酸。 蛋氨酸,镁,维生素C,铁,P5P和烟酸,以及负责从同型半胱氨酸(5-甲基THF,甲基钴胺素和甜菜碱)再生SAMe的辅因子,是最佳肉毒碱合成所必需的(图54-7)。
A pivotal enzyme in carnitine synthesis, betaine aldehyde dehydrogenase, is the same enzyme responsible for synthesis of betaine from choline. Studies suggest this enzyme has a prefer-ence for the cholinebetaine conversion, and that choline sup-plementation may decrease carnitine synthesis; therefore, it may be of greater benefit to supplement with betaine rather than its precursor, choline.40,41
肉碱合成中的关键酶甜菜碱醛脱氢酶与负责从胆碱合成甜菜碱的酶相同。 研究表明,这种酶优先选择胆碱 - 甜菜碱, 补充胆碱可能会降低肉碱的合成; 因此,补充甜菜碱而不是其前体胆碱可能更有益处。40,41
Chondroitin Sulfates, Glucosamine Sulfate, and Other Sulfated Proteoglycans 硫酸软骨素,硫酸葡萄糖胺和其他硫酸化蛋白多 糖
Proteoglycans are amino sugars found in all tissues, the highest being in cartilage, tendons, ligaments, synovial fluid, skin, fingers, toenails, heart valves, and the basement membrane of all blood vessels. Perhaps the most widely known of the amino sugars are the chondroitin sulfates and glucosamine sulfate (see Chapter 94 for further discussion).
蛋白多糖是在所有组织中发现的氨基糖,最高的是在软骨,肌腱, 韧带,滑液,皮肤,手指,脚趾甲,心脏瓣膜和所有血管的基底膜中。 也许最广为人知的氨基糖是硫酸软骨素和硫酸氨基葡萄糖(参见第94章进一步讨论)。
Chondroitin sulfates are primarily composed of alternating residues of N-acetyl-d-galactosamine and d-glucuronate. Sul-fate residues are present on C-4 of the galactosamine residues in one type of chondroitin and on C-6 in another. Glucos-amine sulfate is a simple molecule composed of glucose, the amino acid glutamine, and a sulfate group. Other sulfated pro-teoglycans include dermatan sulfates, keratan sulfates, and heparan sulfates.
硫酸软骨素主要由N-乙酰基-d-半乳糖胺和d-葡糖醛酸的交替残基组成。 硫酸盐残基存在于一种软骨素中的半乳糖胺残 基的C-4上,另一种中存在于C-6上。 氨基葡萄糖硫酸盐是由葡萄糖,氨基酸谷氨酰胺和硫酸盐基团组成的简单分子。 其 他硫酸化蛋白多糖包括硫酸皮肤素,硫酸角质素和硫酸乙酰肝素。
High levels of homocysteine are likely to negatively affect the formation of the sulfated amino sugars, because although some sulfates are present in the diet, the sulfoxidation of cysteine is an important source of sulfate molecules. The sulfoxidation pathway proceeds through the toxic intermediate sulfite and requires molybdenum as a cofactor.
高水平的高半胱氨酸可能对硫酸化氨基糖的形成产生负面影响, 因为尽管饮食中存在一些硫酸盐,但半胱氨酸的磺化氧化是硫酸 盐分子的重要来源。 磺化氧化途径通过有毒的中间亚硫酸盐进 行并且需要钼作为辅助因子。
FIGURE 54-8 A, Pantotheine. B, Pantothine. C, Pantothenic acid. D, Cysteamine. 54-8 APantotheine。  BPantothine。  C,泛酸。  D,半胱胺。
Coenzyme A 辅酶A.
CoA consists of an adenine nucleotide and phosphopantetheine. Contained within the structure of this coenzyme is pantothenic acid; however, the reactive component of the molecule is a sulfhy-dryl group that is not contained within the vitamin. To form the sulfhydryl-containing molecule (pantotheine), pantothenic acid must combine with cysteamine. Cysteamine is formed through conjugation and decarboxylation reactions of cysteine. The disul-fate form of pantetheine, known as pantethine, as opposed to pan-tothenic acid, bypasses cysteine conjugation and decarboxylation. This might account for some of the clinical benefits seen with pan-tethine supplementation that have not been reproduced with the supplementation of pantothenic acid (Figure 54-8, A to D, for the chemical structures of pantotheine, pantothine, pantothenic acid, and cysteamine).
CoA辅酶A.由腺嘌呤核苷酸和磷酸泛酰巯基乙胺组成。 该辅酶结构中含有泛酸; 然而,该分子的反应性成分是维生素中不含的巯基。 为了形成含巯基的分子(泛酰巯基乙胺),泛酸必须与半胱胺结合。 通过半胱氨酸的缀合和脱羧反应形成半胱胺。 与泛酸相反,泛酸形式的pantetheine(称为泛硫乙胺)绕过半胱氨酸缀合和脱羧。这可能解释了泛酸盐补充剂所带来的一些临床益处,这些益处尚未通过补充泛酸而复制(图54-8AD,关于pantotheinepantothine,泛酸和半胱胺的化学结构)。
Coenzyme Q10 辅酶Q10
CoQ10 is a fat-soluble quinone occurring in the mitochondria of each cell (see Chapter 79 for a full discussion). The primary bio-chemical action of CoQ10 is as a cofactor in the electron transport chain, the biochemical pathway that generates adenosine triphos-phate. Because most cellular functions depend on an adequate supply of adenosine triphosphate, CoQ10 is essential for the health of virtually all human tissues and organs. CoQ10 also functions as an antioxidant, assisting in the recycling of vitamin E.42,43
Co Q10是一种脂溶性醌,存在于每个细胞的线粒体中(详见第79 章)。  CoQ10的主要生化作用是作为电子传递链中的辅因子,即产生三磷酸腺苷的生化途径。 由于大多数细胞功能依赖于三磷酸腺苷的充足供应,CoQ10对于几乎所有人体组织和器官的健康都是必不可少的。 辅酶Q10也可作为抗氧化剂,有助于维生素E的再循环。42,43
Biosynthesis of CoQ10 begins with the amino acid tyrosine. Pantothenic acid, P5P, and vitamin C are all required for the initial steps in its synthesis. An isoprenyl side chain from farne-syl diphosphate, an intermediate in cholesterol synthesis between 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) and squalene, is then added. An inadequate supply of this intermedi-ate, which can be caused by HMG-CoA reductase inhibitors (cholesterol-lowering drugs of the statin family), results in decreased levels of CoQ10.44
CoQ10的生物合成始于氨基酸酪氨酸。 泛酸,P5P和维生素C 都是其合成的初始步骤所必需的。 然后加入来自法呢基二磷酸的异戊二烯基侧链,其为3-羟基-3-甲基戊二酰-CoAHMG-CoA)和角鲨烯之间的胆固醇合成中间体。 由HMG-CoA还原酶抑制剂(他汀类药物降胆固醇药物)引起的这种中间体供应不足导致CoQ10水平降低。44
In two of the final steps in the synthesis of CoQ10, methyl groups are provided by SAMe (Figure 54-9). Adequate dietary methionine and a sufficient supply of the nutrients required for the remethylation of homocysteine to methionine (5-methylTHF, methylcobalamin, and betaine) are required to generate suffi-cient SAMe. Suboptimal amounts of SAMe may negatively affect the bodys ability to synthesize sufficient CoQ10. This relation-ship between SAMe and CoQ10 has been suggested in various animal studies.45,46
CoQ10合成的两个最后步骤中,SAMe提供甲基(图54-9)。 需要足够的膳食蛋氨酸和足够供应的高半胱氨酸重新甲基化成甲硫氨酸(5-甲基THF,甲基钴胺素和甜菜碱)以产生足够 的SAMe。 次优量的SAMe可能会对身体合成足够CoQ10的能力产生负面影响。 在各种动物研究中已经提出了SAMeCoQ10之间 的这种关系。45,46
Creatine 肌酸
In humans, more than 95% of the total creatine content is located in skeletal muscle, of which approximately one third is in its free form as creatine, also known as methyl-guanidinoacetic acid,whereas the remainder is present in a phosphorylated form as cre-atine phosphate (also called phosphocreatine). Creatine phosphate is used within skeletal muscle as a means of storing high-energy phosphate bonds.
在人类中,超过95%的总肌酸含量位于骨骼肌中,其中约三分之一是游离形式的肌酸,也称为甲基胍基乙酸,而其余部分以磷酸化形式存在,如磷酸肌酸(也称为磷酸肌酸)。 磷酸肌酸在骨骼肌中用作储存高能磷酸盐键的手段。
Creatine is formed in the liver, kidney, and pancreas, beginning with the combination of arginine and glycine to produce guanidi-noacetate. A methyl group from SAMe is then transferred, result-ing in the formation of creatine. The by-product of this reaction, S-adenosylhomocysteine, is subsequently hydrolyzed into homo-cysteine and adenosine. To optimize endogenous production of creatine, the amino acids arginine, glycine, and methionine must be available as substrates. Additionally, cofactors needed to opti-mize remethylation of homocysteine to form methionine are required to recycle the homocysteine to methionine for reuse as SAMe (Figure 54-10). Serum creatine levels have been positively correlated with plasma homocysteine levels (i.e., as creatine levels rise, so do homocysteine levels).47
肌酸在肝脏,肾脏和胰腺中形成,从精氨酸和甘氨酸的组合开始,产生鸟嘌呤 - 乙酸盐。 然后转移来自SAMe的甲基,导致肌酸的形成。 随后将该反应的副产物S-腺苷高半胱氨酸水解成高半胱氨酸和腺苷。 为了优化肌酸的内源性产生,氨基酸精氨酸,甘氨酸和蛋氨酸必须可用作底物。 此外,需要优化同型半胱氨酸重新甲基化以形成甲硫氨酸的辅助因子将同型半胱氨酸再循环至甲硫氨酸以再次用作SAMe(图54-10)。 血清肌酸水平与血浆同型半胱氨酸水平呈正相关(即肌酸水平升高,同型半胱氨酸水平升高)。47
FIGURE 54-9 Synthesis of coenzyme Q10.
FIGURE 54-10 Synthesis of creatine, creatine phosphate, and creatinine.
Epinephrine and Melatonin 肾上腺素和褪黑激素
Derivatives of the aromatic amino acids, l-tyrosine and l-tryptophan, require methylation for the biosynthesis of their down-line metabolites.The biosynthesis of catecholamines begins with the amino acid l-tyrosine and proceeds through dopa and dopamine, resulting in the formation of norepinephrine, the neurotransmitter substance found in most sympathetic nerve terminals, as well as in some synapses of the CNS. In the chromaffin cells of the adrenal medulla, a methyl group is provided by SAMe, resulting in the formation of epinephrine from norepinephrine. A number of metabolites are formed from the degradation of both norepineph-rine and epinephrine. Catecholamine degradation proceeds inde-pendently, and in conjunction with monoamine oxidase, by catechol-O-methyltransferase. This enzyme catalyzes the transfer of a methyl group donated by SAMe and, depending on the sub-strate, results in the formation of homovanillic acid, normeta-nephrine, and metanephrine.
The formation of melatonin from l-tryptophan proceeds through 5-hydroxytryptophan, serotonin, and N-acetylserotonin. Melato-nin is then formed in the pineal gland by the donation of a methyl group. 5-Methoxytryptamine, an alternate metabolite of serotonin, also requires the addition of a methyl group.
芳香族氨基酸,L-酪氨酸和L-色氨酸的衍生物需要甲基化以用于其下游代谢物的生物合成。儿茶酚胺的生物合成以L-酪氨酸开始,并通过多巴和多巴胺进行,导致去甲肾上腺素的形成,去甲肾上腺素是在大多数交感神经末梢中发现的神经递质物质,以及在CNS的一些突触中。在肾上腺髓质的嗜铬细胞中,SAMe提供甲基,导致去甲肾上腺素形成肾上腺素。 去甲肾上腺素和肾上腺素的降解形成许多代谢物。 儿茶酚胺降解独立地进行,并且与单胺氧化酶一起通过儿茶酚-O-甲基转移酶进行。 该酶催化SAMe捐赠的甲基的转移,并且取决于底物,导致形成高香草酸,去甲变肾上腺素和变肾上腺素。从L-色氨酸形成褪黑激素通过 5-羟色氨酸,5-羟色胺和N-乙酰血清素。 然后通过捐赠甲基在松果体中形成褪黑激素。  5-甲氧基色胺,5-羟色胺的替代代谢产物,也需要加入甲基。
Phosphatidylcholine 磷脂酰胆碱
Phosphatidylcholine (PC) is a primary component of lecithin. It is the most frequently encountered phospholipid in animals and is structurally related to phosphatidylserine and phosphatidyl-ethanolamine. PC consists of a glycerol backbone that is esteri-fied with fatty acids on carbon atoms 1 and 2, and with a phosphoric acid/choline complex in position 3. Although PC is usually referred to as if it were a single compound, it is actually a group of related compounds that vary depending on the fatty acid composition at positions C-1 and C-2.
磷脂酰胆碱(PC)是卵磷脂的主要成分。 它是动物中最常遇到的磷脂,并且在结构上与磷脂酰丝氨酸和磷脂酰乙醇胺有关。 PC由碳原子12上的脂肪酸酯化的甘油骨架和3位的磷酸/胆碱络 合物组成。虽然PC通常被称为单一化合物,但它实际上是一组相 关化合物的含量根据C-1C-2位的脂肪酸组成而变化。
Dietary choline is derived primarily from PC, which, after absorption by the intestinal mucosa, is metabolized to choline in the liver by the enzyme phospholipase D. Most choline is rephos-phorylated to PC; however, a small amount is carried to the brain via the bloodstream, where it is converted to the neurotransmitter acetylcholine. If PC or choline is lacking in the diet, it can be synthesized from phosphatidylserine and phosphatidylethanol-amine (see Figure 54-5). Synthesis of PC depends on the avail-ability of SAMe as a methyl donor, because synthesis involves the transfer of methyl groups from three SAMe molecules to phospha-tidylethanolamine to generate one molecule of PC.
膳食胆碱主要来自PC,其在被肠粘膜吸收后被磷脂酶D代谢成肝脏中的胆碱。大多数胆碱被再磷酸化为PC; 然而,少量通过血流传递到大脑,在那里它被转化为神经递质乙酰胆碱。如果饮食中缺乏PC或胆碱,它可以由磷脂酰丝氨酸和磷脂酰乙醇胺合成(见图54-5)。  PC的合成取决于SAMe作为甲基供体的可用性,因为合成涉及将甲基从三个SAMe分子转移至 磷脂酰乙醇胺以产生一个PC分子。
The metabolic pathways of PC, methionine, methylcobalamin, and 5-methylTHF are interrelated, intersecting at the regeneration of methionine from homocysteine by betaine (see Figure 54-1). The use of choline molecules as methyl donors in this process is probably the main factor that determines how rapidly a diet defi-cient in choline induces pathologic changes.25
PC,甲硫氨酸,甲钴胺的代谢途径, 和5-甲基THF相互关联,在再生时相交来自甜菜碱的高半胱氨酸的蛋氨酸(参见图54-1)。 在这个过程中使用胆碱分子作为甲基供体可能是决定胆碱缺乏的饮 食诱导病理变化的主要因素。25
Taurine 牛磺酸
Taurine is a unique amino acid because it carries a sulfonic acid group (SO3H) instead of a carboxyl group (CO2H). Taurine is biosynthesized from methionine or from cysteine via the transsul-furation pathway (see Figure 54-6). Once cysteine is generated, it can be directed into several different pathways, including synthesis of GSH, acetyl CoA, 3-phosphate 5-phosphosulfate (PAPS), and taurine. The committed first step in the degradation of homo-cysteine requires cystathionine synthase, P5P, and serine. P5P is also required as a cofactor in the cleavage of cystathionine to cyste-ine. Homocystinuria, resulting from an absence of cystathionine synthase, can lead to mental retardation. Low levels of cystathio-nine synthase can also lead to abnormally high levels of homocys-teine, especially when remethylation cofactors are also deficient.
牛磺酸是一种独特的氨基酸,因为它带有磺酸基(-SO3H)而不是羧基(-CO2H)。 牛磺酸通过转硫途径从甲硫氨酸或半胱氨酸生物合成(见图54-6)。 一旦产生半胱氨酸,它可以被导 入几种不同的途径,包括GSH,乙酰CoA3'-磷酸5'-磷酸硫酸 盐(PAPS)和牛磺酸的合成。 降解同型半胱氨酸的第一步需 要胱硫醚合成酶,P5P和丝氨酸。  P5P也需要作为胱硫醚裂解 为半胱氨酸的辅助因子。 由于缺乏胱硫醚合酶而导致的高胱氨酸尿症可导致精神发育迟滞。 低水平的胱硫醚合成酶也可导致异常高水平的高半胱氨酸,特别是当再甲基化辅助因子也缺乏时。
Phase 2 Detoxication 肝脏第二阶段排毒
Because homocysteine is a critical intermediate in both methyl and sulfur group metabolism, elevated levels could indicate nutri-ent deficiencies that might compromise function in virtually all of the hepatic phase 2 detoxification reactions.
Amino acid conjugation reactions require either glycine, gluta-mine, or taurine. Glycine functions in the conjugation of aromatic acids (e.g., benzoic acid to hippuric acid). Elevated levels of homo-cysteine might indicate reduced nutritional levels of betaine and subsequently its down-line metabolite, glycine. Taurine functions in acylations (e.g., bile conjugation).
Sulfur conjugation requires NAC, GSH, PAPS, or methionine/ cysteine. NAC is used for mercapturic acid synthesis and is involved in detoxification of a wide variety of compounds, includ-ing aromatic hydrocarbons, some phenols, halides, esters, epox-ides, and caffeine. GSH is involved in dismutation reactions of organic nitrates (e.g., nitroglycerin). PAPS is used in sulfate ester synthesis, mostly with phenols, and some aliphatic alcohols (e.g., ethanol) and aromatic amines. Methionine and cysteine are used in cyanide-thiocyanate detoxification. A portion of the inorganic sulfur needed for the formation of all of these compounds passes through the homocysteine cycle.
氨基酸缀合反应需要甘氨酸,谷氨酰胺或牛磺酸。 甘氨酸在芳族酸(例如,苯甲酸与马尿酸)的缀合中起作用。 同型半胱氨酸水平升高可能表明甜菜碱及其下游代谢产物甘氨酸的营养水平降低。 牛磺酸在酰化中起作用(例如,胆汁结合)。硫结合需要NACGSHPAPS或蛋氨酸/半胱氨酸。  NAC用于巯基尿酸合成,并且涉及多种化合物的解毒,包括芳香烃,一些酚,卤化物,酯,环氧化物和咖啡因。  GSH参与有机硝酸盐(例如 硝酸甘油)的歧化反应。  PAPS用于硫酸酯合成,主要使用酚类 和一些脂肪醇(例如乙醇)和芳族胺。 蛋氨酸和半胱氨酸用于 氰化物 - 硫氰酸盐解毒。 形成所有这些化合物所需的一部分无 机硫通过高半胱氨酸循环。
Alkylation reactions require SAMe, methylcobalamin, or 5-methylTHF. These compounds provide methyl groups to detox-ify compounds containing hydroxide, SH, or NH2 groups. Exam-ples of these reactions include norepinephrine to epinephrine, epinephrine to metanephrine, guanidoacetic acid to creatine, and N-acetylserotonin to melatonin.
烷基化反应需要SAMe,甲基钴胺素或5甲基THF。 这些化合物提供甲基以解毒含有氢氧化物,SHNH2基团的化合物。 这些反应的实例包括去甲肾上腺素至肾上腺素,肾上腺素至变肾上腺素,胍乙酸至肌酸,以及N-乙酰血清素至褪黑激素。
Other phase 2 detoxification reactions that might be affected by elevated homocysteine as a biological marker of reduced nutrient formation include acetylation by acetyl CoA, which requires cys-teine as a source of its cysteamine component, and the use of car-nitine for the conversion of valproic acid to valpropylcarnitine.
Heart Disease 心脏病
Increased blood levels of homocysteine are correlated with sig-nificantly increased risk of coronary artery disease (CAD),48-54 myocardial infarction,55,56 peripheral occlusive disease,57-60 cerebral occlusive disease,57,60 and retinal vascular occlusion (Box 54-1).61
血液中同型半胱氨酸水平升高与冠状动脉疾病(CAD),48-54心 肌梗死55,56外周闭塞性疾病57-60的风险显着增加相关。脑闭塞性疾病57,60和视网膜血管闭塞(方框54-1)。61
BOX 54-1 What Homocysteine and Homocysteine Thiolactone Do to Arteries 方框54-1什么是同型半胱氨酸和同型半胱氨酸硫代 内酯对动脉的影响
Generate superoxide and hydrogen peroxide, which have been linked to damage to arterial endothelium产生超氧化物歧化酶和过氧化氢,它们与动脉内皮受损有关。
Change coagulation factor levels so as to encourage clot formation改变凝血因子水平,以促进凝块的形成
Prevent small arteries from dilating, so they are more vulnerable to obstruction 防止小动脉扩张,使其更容易被阻塞。
Cause smooth muscle cells in the arterial wall to multiply 使动脉壁平滑肌细胞增殖
Interact with low-density lipoproteins, causing them to precipitate and damage endothelial tissue与低密度脂蛋白相互作用,使其沉淀并破坏内皮组织。
Cause platelets to aggregate 使血小板聚集
Inborn errors of homocysteine metabolism result in high lev-els of homocysteine in the blood and severe atherosclerotic dis-ease; even within the range considered normal (4 to 16 μmol/L), there is a graded increase in risk for CAD. In a study of 304 patients with CAD versus controls, the odds ratio for CAD increased as plasma homocysteine increased, even within the normal range. A 5 μmol/L increase in plasma homocysteine was correlated with an increase in the odds ratio of 2.4 (P <0.001), with no threshold effect.51
同型半胱氨酸代谢的先天性错误导致血液中高水平的同型半胱氨酸和严重的动脉粥样硬化疾病; 即使在正常范围内(416μmol/ L),CAD的风险也会增加。 在一项对304CAD患者与 对照组患者的研究中,CAD的优势比随着血浆同型半胱氨酸的增加而增加,即使在正常范围内也是如此。 血浆同型半胱氨酸增 加5μmol/ L与优势比增加2.4相关(P <0.001),没有“阈值效应”。51
A review of numerous studies found that mild hyperhomocys-teinemia after a methionine load test occurred in 21%, 24%, and 32% of patients with CAD, cerebrovascular disease, and periph-eral vascular disease, respectively.46 Another group of researchers found a 29.3% incidence of hyperhomocysteinemia (>14 μmol/L by their definition) in a group of 1160 elderly (ages 67 to 96 years) individuals in the Framingham Heart Study. The study also indi-cated that plasma homocysteine levels increased with age.57
许多研究的回顾发现,甲硫氨酸负荷试验后轻度高同型半胱氨酸血症分别发生在21%,24%和32%的CAD,脑血管疾病和外周血管疾病患者中。46另一组研究人员发现29.3Framingham心脏研究中,1160名老年人(年龄6796岁)的人群中高同型半胱氨 酸血症的发生率(按其定义>14μmol/ L)。 该研究还表明血浆 同型半胱氨酸水平随年龄增长而增加。57
A number of interrelated atherogenic mechanisms are thought to be involved with hyperhomocysteinemia. These include advanced thickening and smooth muscle cell proliferation of endothelial vessel wall intima, enhanced lipid deposition in the vessel wall, forced detachment of endothelial cells, activation of leukocytes and thrombocytes, increased low-density lipoprotein oxidation, initiation of platelet thromboxane synthesis, enhanced oxidative stress induced by peroxide formation during homocyste-ine oxidation, and prothrombotic coagulation interference.62,63 One way homocysteine assists this process is by the generation of hydrogen peroxide.64 By creating oxidative damage to low-density lipoprotein cholesterol and endothelial cell membranes, hydrogen peroxide can then catalyze injury to vascular endothelium.64,65
许多相互关联的致动脉粥样硬化机制被认为与高同型半胱氨酸血症有关。 这些包括内皮血管壁内膜的先进增厚和平滑肌细胞增殖,血管壁中脂质沉积增强,内皮细胞强制脱离,白细胞和血小板活化,低密度脂蛋白氧化增加,血小板血栓素合成开始,氧化增强同型半胱氨酸氧化过程中过氧化物诱导的应激和促血栓形成凝血干扰。62,63同型半胱氨酸辅助这一过程的一种方法是产生 过氧化氢。64通过对低密度脂蛋白胆固醇和内皮细胞膜产生氧化损伤,氢过氧化物可以催化对血管内皮的损伤。64,65
Nitric oxide and other oxides of nitrogen released by endothe-lial cells (also known as endothelium-derived relaxing factor) pro-tect endothelial cells from damage by reacting with homocysteine, forming S-nitrosohomocysteine, which inhibits hydrogen perox-ide formation. However, as homocysteine levels increase, this pro-tective mechanism can become overloaded, allowing damage to endothelial cells to occur.65-67 Because of the role of sulfate com-pounds in the formation of amino sugars needed to form the base-ment membrane of blood vessels, high levels of homocysteine are likely to contribute to the formation of blood vessels that are more susceptible to oxidative stress.67 The end result of the combination of oxidative damage and endothelial collagen instability can be the formation of atherosclerotic plaques.
内皮细胞释放的一氧化氮和其他氮氧化物(也称为内皮衍生的 松弛因子)通过与高半胱氨酸反应保护内皮细胞免受损伤,形成抑制过氧化氢形成的S-亚硝基高半胱氨酸。 然而,随着同型半 胱氨酸水平的增加,这种保护机制可能会过载,从而导致内皮细 胞受损。65-67由于硫酸盐化合物在形成血管基底膜所需的氨基糖形成中的作用,同型半胱氨酸可能有助于形成更易受氧化应激影 响的血管。67氧化损伤和内皮胶原不稳定性相结合的最终结果可 能是动脉粥样硬化斑块的形成。
Decreased plasma folate levels are correlated with increased lev-els of homocysteine, as well as a subsequent increased incidence of CAD. In a 15-year Canadian study of CAD mortality in 5056 men  and women ages 35 to 79 years, lower serum folate levels were cor-related with a significantly increased risk of fatal CAD.68 In a cohort from the Framingham Heart Study, concentrations of folate and P5P were inversely correlated with homocysteine levels and the risk of extracranial carotid artery stenosis.57 Low P5P and low vitamin B12 have also been linked with hyperhomocysteinemia and a significantly increased risk of CAD.51 Another study of 160 car-diac transplantation patients followed for an average of 28 days found that the high homocysteine levels seen in 99 of these patients surprisingly demonstrated no causal role in the atherothrombotic vascular complications of transplantation. Vitamin B6 deficiency was seen in 21% of recipients with, and in 9% without, cardiovas-cular complications or death, or both. Compared with patients with normal B6 levels, there was a 2.7-fold increase in untoward cardiac events for those patients with B6 levels less than or equal to 20 nmol/L.69
血浆叶酸水平降低与同型半胱氨酸水平升高以及随后CAD发病率增 加相关。 在一项为期15年的加拿大研究中,5056名男性死于CAD死亡年龄在3579岁之间的女性血清叶酸水平降低与致死性CAD风险 显着增加相关。68Framingham心脏研究的队列中,叶酸和P5P 的浓度与同型半胱氨酸水平和风险呈负相关。颅外颈动脉狭窄。 57P5P和低维生素B12也与高同型半胱氨酸血症和CAD风险显着增加有关。51160例心脏移植患者的另一项研究平均随访28天后发 现在99名这些患者中观察到的高同型半胱氨酸水平令人惊讶地证 明在移植的动脉粥样硬化血栓并发症中没有因果作用。  21%的 受者有维生素B6缺乏,9%没有心血管并发症或死亡,或两者兼 而有之。 与B6水平正常的患者相比,B6水平低于或等于20 nmol / L的患者心脏不良事件增加2.769
Remethylation of homocysteine and the subsequent formation of SAMe are critical for biosynthesis of l-carnitine, CoQ10, and creatine. Similarly, the transsulfuration pathway must be function-ing properly for optimal biosynthesis of cysteine, GSH, pantethine, and taurine. All of these nutrients are used clinically to reduce oxi-dative stress, improve risk factor markers, or treat heart disease.
同型半胱氨酸的再甲基化和随后的SAMe形成对于左旋肉碱, CoQ10和肌酸的生物合成是至关重要的。 类似地,转硫途径必须 适当地起作用以最佳地生物合成半胱氨酸,GSH,泛硫乙胺和牛 磺酸。 所有这些营养素在临床上用于减少氧化应激,改善风险 因子标记或治疗心脏病。
Plasma S-adenosylhomocysteine is a more sensitive indicator of cardiovascular disease than plasma homocysteine.18
血浆S-腺苷同型半胱氨酸是比血浆同型半胱氨酸更敏感的心血管 疾病指标。18
Peripheral Vascular Disease 周边血管疾病
Elevated homocysteine levels have been established as an indepen-dent risk factor for intermittent claudication and deep vein throm-bosis. Elevated homocysteine levels corresponded with an increased incidence of intermittent claudication and decreased serum folate levels in a study of 78 patients with intermittent clau-dication.70 A four-fold increase in risk of peripheral vascular dis-ease was noted in individuals with hyperhomocysteinemia compared to those with normal homocysteine levels.71 A group of researchers in the Netherlands found high homocysteine levels to be a significant risk factor for deep vein thrombosis, with a stron-ger relationship among women than men.72
已确定升高的同型半胱氨酸水平是间歇性跛行和深静脉血栓形成的 独立危险因素。 78例间歇性跛行患者的研究中,同型半胱氨酸水 平升高与间歇性跛行发生率增加和血清叶酸水平降低相关。70高同型 半胱氨酸血症患者的外周血管疾病风险增加4倍。正常的同型半胱氨 酸水平。71荷兰的一组研究人员发现高同型半胱氨酸水平是深静脉血 栓形成的重要危险因素,女性之间的关系比男性更强。72
An increased risk of peripheral vascular occlusion was noted in women taking oral contraceptives, which might be linked to the sig-nificantly increased homocysteine levels in women so affected. It is already known that oral contraceptives can cause declines or deficien-cies in vitamins B6, B12, and folate, nutrients integral to the process-ing of homocysteine. Laboratory assessment of plasma homocysteine levels may be helpful to detect women who may be predisposed to peripheral vascular occlusion while on oral contraceptives.73
服用口服避孕药的女性患外周血管闭塞的风险增加,这可能与 受影响的女性的同型半胱氨酸水平显着增加有关。 众所周知, 口服避孕药会引起维生素B6B12和叶酸的下降或缺乏,这是同型 半胱氨酸加工过程中不可或缺的营养素。 血浆同型半胱氨酸水 平的实验室评估可能有助于检测在口服避孕药时可能易患外周血 管闭塞的女性。73
Stroke 中风
Stroke patients have significantly elevated homocysteine levels com-pared to age-matched controls,74 with a linear relationship between risk of stroke and homocysteine levels75 and a significant decrease in blood folate concentrations in those with elevated homocysteine.76 One investigation revealed that people with a dietary intake of at least 300 mcg/day of folic acid reduced their risk of stroke and heart disease by 20% and 13%, respectively, compared with those who consumed less than 136 mcg of folic acid per day.77
与年龄匹配的对照组相比,中风患者的同型半胱氨酸水平显着升高74, 中风和同型半胱氨酸水平之间存在线性关系75,同型半胱氨酸水平升 高的患者血液叶酸浓度显着降低76研究显示,与每天摄入少于136 mcg 叶酸的人相比,饮食摄入量至少为300 mcg /天的叶酸患者,卒中和心 脏病的风险分别降低了20%和13%。 TF754
Pregnancy 怀孕
Biochemical enzyme defects and nutritional deficiencies are receiving increasing attention for their role in causing neural tube defects (NTDs), as well as other negative pregnancy outcomes,including spontaneous abortion, placental abruption (infarct), preterm delivery, and low infant birth weight. Evidence has sug-gested that derangement of methionine-homocysteine metabo-lism could be the underlying mechanism of pathogenesis of NTDs and might be the mechanism of prevention observed with supple-mentation of folic acid.78,79 It has been firmly established that a low dietary intake of folic acid increases the risk for delivery of a child with an NTD and that periconceptional folic acid supple-mentation reduces the occurrence of NTDs.80-86 Research also indicates that supplemental folic acid intake results in increased infant birth weight and improved Apgar scores, along with a concomitant decreased incidence of fetal growth retardation and maternal infections.87-90A derangement in methionine-homocysteine metabolism has also been correlated with recurrent miscarriage and placental infarcts (abruption).91
生化酶缺陷和营养缺乏因其在引起神经管缺陷(NTDs)以及 其他阴性妊娠结局中的作用而越来越受到关注,包括自然流产,胎盘早剥(梗塞),早产和低婴儿出生体重。 有证据表明,蛋氨酸 - 同型半胱氨酸代谢的紊乱可能是NTD发病 机制的潜在机制,可能是叶酸补充后预防的机制。78,79已经确定 叶酸摄入量低增加NTD儿童分娩和围孕期补充叶酸的风险可以减 少NTDs的发生。80-86研究还表明,补充叶酸摄入会导致婴儿出生 体重增加和Apgar评分提高,同时伴随发病率下降胎儿生长迟缓 和母体感染87-90甲硫氨酸 - 同型半胱氨酸代谢的紊乱也与复发性 流产和胎盘梗塞(中断)有关。91
The amino acid homocysteine, when elevated, might be a tera-togenic agent contributing to congenital defects of the heart and neural tube. Evidence from experimental animals lends support to this belief. When avian embryos were fed homocysteine to raise serum homocysteine to over 150 nmol/mL, dysmorpho-genesis of the heart and neural tube, as well as of the ventral wall, was observed.92
当氨基酸同型半胱氨酸升高时,可能是导致心脏和神经管先天 性缺陷的致畸剂。 来自实验动物的证据支持这一信念。 当给予 禽胚胎同型半胱氨酸以将血清同型半胱氨酸升高至超过150nmol / mL时,观察到心脏和神经管以及腹壁的畸形发生。92
Because homocysteine metabolism, through the remethylation and transsulfuration pathways, affects several biochemical path-ways involving the production of nutrients that are essential to the optimal functioning of the cardiovascular, skeletal, and nervous systems, it is not surprising that these other nutrients have been linked to complications of pregnancy in animal models and humans. Low plasma vitamin B12 levels have been shown to be an independent risk factor for NTD.93,94 Methionine has been shown to reduce the incidence of NTD by 41% in an animal model when administered on days 8 and 9 of pregnancy.95,96 This evidence indicates that a disturbance in the remethylation path-way with a subsequent decrease in SAMe may be a contributing factor to these complications of pregnancy.
因为同型半胱氨酸代谢通过重新甲基化和转硫化途径影响了几 种生化途径,这些途径涉及对心血管,骨骼和神经系统的最佳功 能至关重要的营养素的产生,所以这些其他营养素与并发症有关 并不奇怪怀孕在动物模型和人类。 低血浆维生素B12水平已被证 明是NTD的独立危险因素。93,94在妊娠第8天和第9天给药时,甲 硫氨酸已被证明可以降低动物模型中NTD的发生率41%。 95,96该 证据表明,再甲基化途径的紊乱随后SAMe的减少可能是这些妊娠 并发症的一个促成因素。
PC, due to its role as a precursor to acetylcholine and cho-line, is acknowledged as a critical nutrient for brain and nerve development and function.97-99 Because the metabolic path-ways of choline (via betaine), methionine, methylcobalamin, and 5-methylTHF are interrelated, intersecting at the regen-eration of methionine from homocysteine, a disturbance in the metabolism of either of these two methyl-donor pathways, due to limited availability of key nutrients or decreased enzyme activity, directly affects the bodys ability to optimize levels of SAMe.
PC由于其作为乙酰胆碱和胆碱的前体的作用,被认为是大 脑和神经发育和功能的关键营养素。97-99因为胆碱(通过甜 菜碱),蛋氨酸,甲钴胺和5-甲基THF的代谢途径由于关键 营养素的有限可用性或酶活性降低,这两种甲基供体途径中 的任一种代谢受到干扰,直接影响身体优化SAMe水平的能力 是相互关联的,与同型半胱氨酸的蛋氨酸再生相交。
Evidence suggests that women with a history of NTD-affected pregnancies have altered folic acid metabolism.100-103 Patients with a severe congenital deficiency of the enzyme MTHFR, which is needed for the formation of 5-methylTHF, have reduced levels of both methionine and adenosylmethionine in their cerebrospi-nal fluid and show demyelination in the brain and degeneration of the spinal cord.2,104 Because of its direct impact in the activation of folic acid to its methyl derivative, a milder version of this enzyme defect is also strongly suspected to increase the incidence of NTDs.105
有证据表明,有NTD感染妊娠史的女性会改变叶酸代谢。100-103 患有MTHFR的严重先天性缺陷的患者,这是形成5-甲基-THF所必 需的,其甲硫氨酸和甲硫氨酸水平均降低。腺苷甲硫氨酸在其脑 脊液中表现为脑内脱髓鞘和脊髓变性。2,104由于其对叶酸活化的 影响直接影响其甲基衍生物,这种酶缺陷的较温和版本也被强烈 怀疑增加NTDs的发病率。105
It is established that high vitamin A intake during the first 2 months of pregnancy is associated with a several-fold higher incidence of birth defects.106,107 Although the mechanism of action remains to be elicited, in an animal model, the activity of hepatic MTHFR was suppressed with high vitamin A levels, suggesting that its teratogenic effect during early pregnancy might be associated with a subsequent derangement in the remethylation of homocysteine.108
据证实,妊娠前2个月维生素A摄入量高,出生缺陷发生率 高几倍。106,107虽然在动物模型中仍有引起作用的机制,但肝 脏的活动仍然存在。 MTHFR受到高维生素A水平的抑制,表明 其在妊娠早期的致畸作用可能与随后同型半胱氨酸重新甲基 化的紊乱有关。108
Because a more significant correlation has been found between high homocysteine levels in women experiencing placental abrup-tion, infarction, and spontaneous abortion than in control women, and homocysteine and CoQ10 synthesis depend on the methio-nine-SAMe-homocysteine pathway, it is possible that low CoQ10 and elevated homocysteine independently found in complicated pregnancy may also be found in related conditions.109,110
因为在胎盘早剥,梗塞和自然流产的女性中高同型半胱氨酸水 平与对照女性之间存在更显着的相关性,并且同型半胱氨酸和 CoQ10合成依赖于蛋氨酸-SAMe-高半胱氨酸途径,所以有可能在相 关病症中也可发现低CoQ10和复杂妊娠中独立发现的同型半胱氨酸 升高。109,110
Nutritional intervention with the cofactors required for optimal metabolism of the methionine-homocysteine pathways offers a new integrated possibility for primary prevention of NTD and several other complications of pregnancy. Supplementation with betaine and the active forms of cobalamin and folic acid, such as methylcobalamin and folinic acid, along with riboflavin-5-phosphate (because of its role as a cofactor for the MTHFR enzyme), may play a significant role in reducing or preventing these emotionally devastating outcomes.
用于甲硫氨酸 - 高半胱氨酸途径最佳代谢所需的辅因子的营养干预为初级预防NTD和其他一些妊娠并发症提供了新的综合可 能性。 补充甜菜碱和钴胺素和叶酸的活性形式,如甲钴胺和亚叶酸,以及核黄素-5'-磷酸盐(由于其作为MTHFR酶的辅助因子 的作用),可能在减少或预防中发挥重要作用这些情绪破坏性的 结果。
Neurologic and Mental Disorders 神经和精神疾病
In addition to the known impact of homocysteine on the cardio-vascular system and micronutrient biochemical pathways, numer-ous diseases of the nervous system are correlated with high homocysteine levels and alterations in vitamin B12, folate, or vita-min B6 metabolism, including depression, schizophrenia, multi-ple sclerosis, Parkinsons disease, Alzheimers disease (AD), and cognitive decline in the elderly.
除了同型半胱氨酸对心血管系统和微量营养素生化途径的已知影响外,许多神经系统疾病与高同型半胱氨酸水平和维生素B12,叶酸或维生素B6代谢的改变相关,包括抑郁症,精神分裂症, 多发性硬化症,帕金森病,阿尔茨海默病(AD)和老年人认知能力下降。
Methylation reactions via SAMe, including methylation of DNA and myelin, are vitally important in the CNS. The neuro-logic complications of vitamin B12 deficiency are likely due to a reduction of activity of the vitamin B12-dependent enzyme methi-onine synthase and the subsequent reduction of SAMe produc-tion. The CNS lacks the alternate betaine pathway of homocysteine remethylation; therefore, if methionine synthase is inactivated, the CNS has a greatly reduced methylation capacity.111 Other causes of reduced methionine synthase activity include folic acid defi-ciency and nitrous oxide anesthesia exposure.112
通过SAMe的甲基化反应,包括DNA和髓磷脂的甲基化,在 CNS中是至关重要的。 维生素B12缺乏的神经系统并发症可能 是由于维生素B12依赖性酶蛋氨酸合酶的活性降低以及随后 SAMe产生的减少。  CNS缺乏同型半胱氨酸重新甲基化的替代 甜菜碱途径; 因此,如果甲硫氨酸合酶失活,则CNS的甲基化 能力大大降低。111甲硫氨酸合酶活性降低的其他原因包括叶 酸缺乏和氧化亚氮麻醉暴露。112
Homocysteine has also been found to be a neurotoxin, espe-cially in conditions in which glycine levels are elevated, includ-ing head trauma, stroke, and vitamin B12 deficiency.113 Homocysteine interacts with the N-methyl-d-aspartate receptor, causing excessive calcium influx and free radical production, resulting in neurotoxicity.94 The neurotoxic effects of homocys-teine or reduced methylation reactions, or both, in the CNS contribute to the mental symptomatology seen in vitamin B12 and folate deficiency. Increased homocysteine levels can also be seen in schizophrenics.114
同型半胱氨酸也被发现是一种神经毒素,特别是在甘氨酸水平升高的情况下,包括头部创伤,中风和维生素B12缺乏。 113同型半胱氨酸与N-甲基-d-天冬氨酸受体相互作用,引起过量的钙内流和自由基的产生,导致神经毒性。94同型半胱氨酸或减少的甲基化反应或两者的神经毒性作用在CNS中导致维 生素B12和叶酸缺乏症中出现的精神症状。 在精神分裂症患者 中也可以看到同型半胱氨酸水平升高。114
Significant deficiencies in vitamin B12 and folate are common in the elderly population and can contribute to a decline in cognitive function.115-117 An investigation of cognitive ability in older men (54 to 81 years old) found poorer spatial copying skills in those with higher homocysteine levels. Better memory performance was correlated with higher vitamin B6 levels.118
维生素B12和叶酸的显着缺陷在老年人群中很常见,并且可能导致认知功能下降。115-117对老年男性(5481岁)认知能力的调 查发现,空间复制技能较差。具有较高同型半胱氨酸水平的那些。更好的记忆表现与更高的维生素B6水平相关。118
Vitamin B12 deficiency and increasing severity of cognitive impairment have been seen in AD patients compared with con-trols and patients with other dementias.119 In a study of 52 AD patients, 50 hospitalized nondemented controls, and 49 elderly subjects living at home, patients with AD were found to have the highest homocysteine levels and the highest methylmalonic acid (an indicator of vitamin B12 deficiency) levels.120
In another Framingham study cohort with an average of 8 yearsfollow-up, dementia developed in 111 of 1092 nondementia sub-jects, including 83 who were diagnosed with AD. The adjusted relative risk of dementia was 1.4 for each increase of 1 standard deviation in the logarithmically adjusted homocysteine value. The relative risk of AD was 1.8 per increase of 1 standard deviation at baseline and 1.6 per increase of 1 standard deviation 8 years before baseline. Additionally, in those with a plasma homocysteine level that was greater than 14 μmol/L, the risk of AD nearly doubled.121
在另一项平均随访8年的弗雷明汉研究队列中,1092名非痴呆 患者中有111名患有痴呆症,其中83名被诊断患有AD。 每增加1 个标准,调整后的痴呆相对风险为1.4对数调整的同型半胱氨酸值的偏差。  AD的相对风险在基线时每增 加1个标准差为1.8,在基线前8年每增加1个标准差为1.6。 此外,在血浆同型半胱氨酸水平大于14μmol/ L的患者中,AD的风险几乎翻 了一番。121
In a study of 741 psychogeriatric patients, high plasma homo-cysteine levels were found in demented and nondemented patients; however, only demented patients also had lower blood folate concentrations compared with controls. Patients with con-comitant vascular disease had significantly higher plasma homo-cysteine than those without diagnosed vascular disease. Significantly higher homocysteine levels, compared with controls, have also been found in Parkinsons disease patients.122
在一项针对741名精神病患者的研究中,在痴呆和非痴呆患者中发现了高血浆同型半胱氨酸水平; 然而,与对照组相比,只 有痴呆患者的血液叶酸浓度也较低。 伴有血管疾病的患者血浆同型 半胱氨酸水平显着高于未诊断为血管疾病的患者。 与对照组相比,同型半胱氨酸水平显着升高 帕金森病患者也有发现。122
Homocysteines effects on neurotransmitter metabolism, along with its potential reduction of methylation reactions, could be a contributing factor to the etiology of depression. Folate and vita-min B12 deficiency can cause neuropsychiatric symptoms, includ-ing dementia and depression. SAMe is used therapeutically as an antidepressant in Europe and was the third most popular antide-pressant treatment in Italy in 1995.123,124 Long-term treatment of post-stroke survivors with folic acid (2 mg), vitamin B6 (25 mg), and vitamin B12 (0.5 mg) was associated with a reduction in major depression in a 563-patient population, randomized, double-blind, placebo-controlled trial.125
同型半胱氨酸对神经递质代谢的影响, 甲基化反应可能减少,可能是导致抑郁症病因的一个因素。 叶酸和维生素B12缺乏会导致神经精神症状,包括痴呆和抑郁症。 在欧洲,SAMe在治疗上被用作抗抑郁药,并且是1995年在意大利 第三大最受欢迎的抗抑郁药治疗。123,124用叶酸(2 mg),维生素B6长期治疗中风后幸存者(25 mg)维生素B120.5毫克)与563例患者的重度抑郁症减少相关,随机,双盲,安慰剂对照试 验。125
Methylation of myelin basic protein is vital to the maintenance of the myelin sheath. The worst case scenario of folate and vitamin B12 deficiency includes demyelination of the posterior and lateral columns of the spinal cord, a disease process called subacute com-bined degeneration of the spinal cord (SCD).111 SCD can also be precipitated by nitrous oxide anesthesia, which causes an irrevers-ible oxidation of the cobalt moiety of the vitamin B12 molecule and the subsequent inhibition of methionine synthase activity, a decrease in homocysteine remethylation, and decreased SAMe production.112 This has been treated using supplemental methio-nine, which further supports the theory of a nitrous oxideinduced biochemical block at methionine synthase.126 Particularly at risk for this condition are vitamin B12-deficient individuals who visit their dentist and receive nitrous oxide.112,127
髓鞘碱性蛋白的甲基化对于髓鞘的维持是至关重要的。 叶酸和维生素B12缺乏的最坏情况包括脊髓后侧和侧柱的脱髓鞘,一种称为亚急性脊髓联合变性(SCD)的疾病过程。111SCD也可以通过 以下方式沉淀:氧化亚氮麻醉,导致维生素B12分子的钴部分不可 逆氧化,随后抑制蛋氨酸合成酶活性,降低同型半胱氨酸重新甲基化,降低SAMe产生。112这已经过补充治疗蛋氨酸,进一步支持氧化亚氮诱导的蛋氨酸合酶生化阻滞的理论。126特别有风险的是 这种情况的维生素B12缺乏访问他们的牙医和接受一氧化二氮的人。112,127
Abnormal methylcobalamin metabolism is one of the proposed mechanisms for the pathophysiology of the demyelinating disease multiple sclerosis (MS). Deficiency of vitamin B12 has been linked to some cases of MS, and it has been suggested that dietary defi-ciency, or more likely, a defect in R-proteinmediated absorption or methylation of vitamin B12, might be a significant contributor to the pathogenesis of MS.128
甲基钴胺素代谢异常是脱髓鞘疾病多发性硬化(MS)的病理生理学的提出机制之一。 缺乏维生素B12与某些MS病例有关,有人认为饮食缺乏,或更可能是R蛋白介导的维生素B吸收或甲基化12 缺陷,可能是MS的发病机制的重要贡献者。128
Individuals with genetic variation in the 5,10-MTHFR gene are more susceptible to having a psychiatric disorder. The genetic vari-ation MTHFR C677T was significantly associated with schizo-phrenia, bipolar disorder, and unipolar depressive disorder.129
5,10-MTHFR基因中具有遗传变异的个体更容易患有精神疾病。 遗传变异MTHFR C677T与精神分裂症,双相情感障碍和单相抑郁
Diabetes Mellitus 糖尿病
Homocysteine levels appear to be lower in individuals with type 1 diabetes mellitus. Forty-one type 1 diabetic subjects (age 34.8 ± 12 years; duration of illness: 10.7 ± 11.1 years) were compared with 40 age-matched control subjects (age 34.2 ± 9.1 years). After an over-night fast, homocysteine was significantly lower (P = 0.0001) in the diabetic group (6.8 ± 2.2) than in the controls (9.5 ± 2.9). This difference was apparent in male and female subgroups.130 How-ever, increased levels of homocysteine have been reported in type 1 diabetics with proliferative retinopathy131 and nephropathy.131,132
患有1型糖尿病的个体中同型半胱氨酸水平似乎较低。 将411型 糖尿病受试者(年龄34.8±12;病程:10.7±11.1岁)与40名年龄匹配的对照受试者(年龄34.2±9.1岁)进行比较。 禁食过夜后,糖尿病组(6.8±2.2)的同型半胱氨酸显着低于对照组 (9.5±2.9)(P = 0.0001)。 这种差异在男性和女性亚组中是 明显的。130然而,已报道1型糖尿病患者的增殖性视网膜病变131和 肾病的同型半胱氨酸水平升高。131,132
Evidence to date suggests that metabolism of homocysteine is impaired in patients with noninsulin-dependent diabetes mellitus (NIDDM). After a methionine load, hyperhomocyste-inemia occurred with significantly greater frequency in patients with NIDDM (39%) compared with age-matched controls (7%). The area under the curve over 24 hours, reflecting the total period of exposure to increased homocysteine, was also elevated with greater frequency in patients with NIDDM and macrovascular disease (33%) compared with controls (0%). The authors concluded that hyperhomocysteinemia was associ-ated with macrovascular disease in a significant proportion of patients with NIDDM.133 Other researchers reported a corre-lation between increased homocysteine levels and the occur-rence of macroangiopathy in patients with NIDDM. Intramuscular injection of 1000 μg methylcobalamin daily for 3 weeks reduced the elevated plasma levels of homocysteine in these individuals.134
迄今为止的证据表明同型半 胱氨酸的代谢非胰岛素依赖型糖尿病患者受损mellitusNIDDM)。 甲硫氨酸负荷后,与年龄匹配的对照 组(7%)相比,NIDDM患者发生高同型半胱氨酸血症的频率 显着增加(39%)。 与对照组(0%)相比,NIDDM和大血管 疾病患者(33%)在24小时内的曲线下面积反映了暴露于同 型半胱氨酸增加的总时间,其频率也更高。 作者得出结论, 高同型半胱氨酸血症与大部分NIDDM患者的大血管病相关。133 其他研究人员报道了NIDDM患者同型半胱氨酸水平升高与大血 管病变的相关性。 每天肌肉注射1000μg甲钴胺3周,可降低 这些个体血浆中同型半胱氨酸水平的升高。134
Elevated homocysteine levels appear to be a risk factor for dia-betic retinopathy in individuals with NIDDM. This might be due to a point mutation on the gene for the enzyme MTHFR.135,136 A significantly higher percentage of diabetics with retinopathy exhibit this mutation.137 Elevated homocysteine levels cause cell injury to the small vessels, which may contribute to the development of reti-nopathy, as well as macroangiopathy in the cardiovascular system.135
升高的同型半胱氨酸水平似乎是患有NIDDM的个体中糖尿病性视 网膜病变的风险因素。 这可能是由于MTHFR酶基因的点突变造成 的。135,136视网膜病变的糖尿病患者中显着较高的百分比表现出这 种突变。137同型半胱氨酸水平升高导致小血管细胞损伤,这可能 有助于视网膜病变的发展,以及心血管系统中的大血管病变。135
Rheumatoid Arthritis 类风湿关节炎
Elevated total homocysteine levels have been reported in patients with rheumatoid arthritis (RA) and psoriasis. Twenty-eight patients with RA and 20 healthy age-matched control subjects were assessed for homocysteine levels while fasting and in response to a methionine challenge. Fasting levels were 33% higher in RA patients than in controls. Four hours after the methionine chal-lenge, the increase in plasma homocysteine concentration was also higher in patients with RA.137 Another study found statistically significant increases in homocysteine in RA patients (P = 0.003), with 20% of the patients having homocysteine levels above the reference range.138 A mechanism for this increased homocysteine in RA patients has not been elucidated. Penicillamine, a common sulfhydryl-containing arthritis treatment, has been found to lower elevated homocysteine levels in vivo.139
据报道,类风湿性关节炎(RA)和牛皮癣患者的总同型半胱氨酸水平升高。 对28名患有RA的患者和20名健康年龄匹配的对照受 试者在禁食和响应甲硫氨酸攻击时评估同型半胱氨酸水平。  RA 患者的空腹水平比对照组高33%。 在甲硫氨酸攻击后4小时,RA 患者血浆同型半胱氨酸浓度的增加也更高。137另一项研究发现RA 患者中同型半胱氨酸的统计学显着增加(P = 0.003),20%的 患者具有同型半胱氨酸水平高于参考范围。138RA患者中这种增加 的高半胱氨酸的机制尚未阐明。 青霉胺,一种常见的含巯基的 关节炎治疗,已被发现降低体内同型半胱氨酸水平升高。139
Psoriasis 银屑病
One study of 30 psoriasis patients and their matched controls were evaluated for blood concentrations of lipids, lipoproteins, acute phase reactants, homocysteine, and atherothrombotic mark-ers. This study observed that more than 50% of the psoriasis patients had homocysteine levels that were higher than 15 mmol/L, whereas only 20% of the control individuals were above this cutoff point. It was concluded that the mean levels of serum homocysteine, fibrinogen, fibronectin, intercellular adhesion mol-ecules, plasminogen activator inhibitor, and autoantibodies against oxidized low-density lipoprotein were increased in psori-atic patients, whereas tissue plasminogen factor, vitamin B12, and folate levels were decreased significantly.62
30名牛皮癣患者及其匹配对照的一项研究评估了血脂,脂 蛋白,急性期反应物,同型半胱氨酸和动脉粥样硬化血栓形 成标志物的血药浓度。 该研究观察到超过50%的银屑病患者 的同型半胱氨酸水平高于15 mmol / L,而只有20%的对照个 体高于此临界值。 结论:银屑病患者血清同型半胱氨酸,纤 维蛋白原,纤维连接蛋白,细胞间粘附分子,纤溶酶原激活 物抑制剂和抗氧化低密度脂蛋白自身抗体的平均水平增加, 而组织纤溶酶原因子,维生素B12和叶酸水平显着下降。62
Further investigation into both the prevalence of hyperhomo-cysteinemia and the mechanism of action affecting RA and psoria-sis is necessary.
Kidney Failure 肾功能衰竭
Because homocysteine is cleared by the kidneys, chronic renal failure, as well as absolute or relative deficiencies of 5-methylTHF, methylcobalamin, P5P, or betaine results in increased homocysteine levels. In 176 patients with end-stage renal disease on peritoneal or hemodialysis, homocysteine concentrations averaged 26.6 ± 1.5 μmol/L in patients with renal failure compared with 10.1 ± 1.7 μmol/L in normal subjects. Abnormal values exceeded the 95th percentile for normal controls in 149 of the patients with renal failure.140 Data also indicated that plasma homocysteine values represented an independent risk factor for vascular events in patients on peritoneal and hemodialysis. Patients with a homo-cysteine concentration in the upper two quintiles (>27.8 μmol/L) had an independent odds ratio of 2.9 (confidence interval, 1.4 to 5.8; P = 0.007) of vascular complications. Vitamin B levels were also lower in patients with vascular complications than in those without such complications.141
因为同型半胱氨酸被肾脏清除,慢性肾功能衰竭以及5-甲基-THF, 甲基钴胺素,P5P或甜菜碱的绝对或相对缺乏导致同型半胱氨酸 增加水平。 在176例腹膜或血液透析终末期肾病患者中,同型半胱氨 酸浓度平均为26.6±
肾功能衰竭患者1.5μmol/ L10.1±1.7 正常人中μmol/ L.  149例肾功能衰竭患者的正常对照组异 常值超过95%。140数据还表明,血浆同型半胱氨酸值是腹膜和血 液透析患者血管事件的独立危险因素。 上两个五分位数(>27.8 μmol/ L)同型半胱氨酸浓度的患者血管并发症的独立比值比为 2.9(置信区间,1.45.8; P = 0.007)。 血管并发症患者的 维生素B水平也低于没有这些并发症的患者。141
Alcoholism and Ethanol Ingestion 酒精中毒和乙醇摄入
Chronic alcoholism is known to interfere with one-carbon metab-olism. Because of this, it is not surprising to find that mean serum homocysteine levels are two times higher in chronic alcoholics than in nondrinkers (P <0.001). Beer consumers have lower con-centrations of homocysteine compared with drinkers of wine or spirits (P = 0.05). In chronic alcoholics, serum P5P and red blood cell folate concentrations have been shown to be significantly lower than in control subjects.13 Plasma homocysteine was signifi-cantly higher, compared with controls, in 42 active alcoholics hos-pitalized for detoxification. In another group of 16 alcoholics who abstained from ethanol ingestion, plasma homocysteine did not deviate from that of controls.14
已知慢性酒精中毒会干扰一碳代谢。 因此,慢性酗酒者的平均 血清同型半胱氨酸水平比不饮酒者高2倍并不令人惊讶(P <0.001)。 与葡萄酒或烈性酒的饮酒者相比,啤酒消费者的同 型半胱氨酸浓度较低(P = 0.05)。 在慢性酗酒者中,血清P5P 和红细胞叶酸浓度已显示出显着低于对照组。13与对照组相比, 42名活跃的酗酒者因排毒而住院时血浆同型半胱氨酸显着升高。 另一组16名酗酒者戒除乙醇摄入,血浆同型半胱氨酸没有偏离对 照组。14
Feeding ethanol to rats produces prompt inhibition of methio-nine synthase, as well as a subsequent increase in activity of beta-ine homocysteine methyltransferase. Despite the inhibition of methionine synthase, the enhanced betaine homocysteine methyl-transferase pathway uses hepatic betaine pools to maintain levels of SAMe.142 Results indicate that ethanol feeding produces a sig-nificant loss in SAMe in the first week, with a return to normal SAMe levels in the second week. Betaine feeding enhances hepatic betaine pools in control animals, as well as ethanol-fed animals; attenuates the early loss of SAMe in ethanol-fed animals; produces an early increase in betaine homocysteine methyltransferase activ-ity; and generates increased levels of SAMe in both control and ethanol-fed groups.143 It has been shown that minimal supple-mental dietary betaine at the 0.5% level increases SAMe two-fold in control animals and five-fold in ethanol-fed rats. Concomitant with the betaine-generated SAMe, ethanol-induced hepatic fatty infiltration was ameliorated.142 Betaine supplementation also reduces the accumulation of hepatic triglyceride produced after ethanol ingestion.143
向大鼠喂食乙醇产生对甲硫氨酸合酶的迅速抑制,以及随后甜 菜碱高半胱氨酸甲基转移酶活性的增加。 尽管甲硫氨酸合成酶 受到抑制,但增强的甜菜碱同型半胱氨酸甲基转移酶途径使用肝 甜菜碱池来维持SAMe水平。142结果表明乙醇喂养在第一周产生了 显着的SAMe损失,并恢复到正常的SAMe水平。第二周。 甜菜碱 喂养可增强对照动物以及乙醇喂养动物的肝脏甜菜碱池; 减少乙 醇喂养动物中SAMe的早期损失; 产生甜菜碱高半胱氨酸甲基转移 酶活性的早期增加; 对照组和乙醇喂养组均产生增加的SAMe水平。143已显示0.5%水平的最低补充膳食甜菜碱使对照动物的SAMe增 加2倍,乙醇喂养大鼠增加5倍。 伴随甜菜碱产生的SAMe,乙醇 诱导的肝脏脂肪浸润得到改善。142甜菜碱补充剂也减少乙醇摄入 后产生的肝脏甘油三酯的积累。143
Gout 痛风
Although homocysteine levels have been positively correlated with increased uric acid levels,2,144,145 no studies have investigated homocysteine levels in gout patients. It is possible the increased uric acid levels in gout are due to decreased SAMe production because of the reduction in homocysteine recycling. The excess adenosine, which reacts with methionine to form SAMe, is degraded to form uric acid as its end product.
虽然同型半胱氨酸水平与尿酸水平升高呈正相关,但2,144,145没有研 究调查痛风患者的同型半胱氨酸水平。 由于同型半胱氨酸的再循环 减少,痛风中尿酸水平升高可能是由于SAMe产生减少所致。 过量的 腺苷与甲硫氨酸应形成SAMe,被降解形成尿酸作为其最终产物。
Niacin is contraindicated in gout, since it competes with uric acid for excretion.146 Animal studies have shown that increased levels of S-adenosylhomocysteine and, thus homocysteine, cause significant reductions in SAMe-dependent methylation reac-tions.16 Therefore, because degradation of the niacin-containing coenzyme nicotinamide adenine dinucleotide is dependent on methylation by SAMe, and SAMe activity is severely reduced in hyperhomocysteinemia, niacin levels might be higher in these people, resulting in less uric acid excretion, higher uric acid lev-els, and increased gout symptoms in susceptible individuals. This possibility and its mechanism need further investigation.
烟酸在痛风中是禁忌的,因为它与尿酸竞争排泄。146动物 研究表明,S-腺苷同型半胱氨酸和同型半胱氨酸水平升高导 致SAMe依赖性甲基化反应显着减少。16因此,因为含烟酸的 辅酶烟酰胺腺嘌呤二核苷酸的降解依赖于SAMe的甲基化,高同型半胱氨酸血症的SAMe活性严重下降,这些 人的烟酸水平可能更高,导致尿酸排泄减少,尿酸水平升高,易 感个体的痛风症状增加。 这种可能性及其机制需要进一步研究。
Osteoporosis 骨质疏松
Osteoporosis is a common presenting symptom in children with homocystinuria due to cystathionine synthase deficiency, as a result of an autosomal recessive error of sulfur amino metabo-lism.147,148 Individuals with cystathionine synthase deficiency have decreased concentrations of cysteine and its disulfide form, cystine. Because of the role of sulfur compounds in the forma-tion of sulfated amino sugars, disturbed cross-linking of colla-gen has been proposed as a possible mechanism of action. One group of researchers studying 10 patients with homocystinuria found normal synthesis of collagen but a significant reduction of cross links.149
由于硫氨基代谢的常染色体隐性错误,骨质疏松症是由于胱硫醚 合酶缺乏导致高胱氨酸尿症的儿童常见症状。147,148胱硫醚合酶 缺乏的个体半胱氨酸及其二硫化物形式胱氨酸浓度降低。 由于 硫化合物在硫酸化氨基糖形成中的作用,已经提出干扰的胶原交 联作为可能的作用机制。 研究10名高胱氨酸尿症患者的一组研 究人员发现胶原蛋白合成正常,但交叉链接显着减少。149
Because of the correlation between homocystinuria and osteoporosis in children with this amino acidopathy and the increase in homocysteine concentrations in postmenopausal women, several authors have implied that elevated homocyste-ine levels contribute to postmenopausal osteoporosis. The Framingham study of 825 men and 1174 women, ranging from 59 to 91 years old, affirmed this suspicion by evaluating plasma homocysteine levels and relative incident of hip fracture over a period of 16 to 19 years. The mean plasma total homocysteine concentration was 13.4 ± 9.1 μmol/L with 41 hip fractures among men and 12.1 ± 5.3 μmol/L and 146 hip fractures among women. It was shown that both men and women in the highest quartile of plasma homocysteine had a greater risk of hip fracture than those in the lowest quartile, where the risk was almost 4 times as high for men and 1.9 times as high for women.150 Because physical activity is well known to lower homocysteine, as well as prevent falls, it may therefore influence the association between homocysteine levels and the risk of frac-ture.15 Therefore, it seems prudent to prescribe exercise, as well as appropriate supplemental therapies for women and men with high homocysteine and osteopenia/osteoporosis.
由于这种氨基酸病患儿的高胱氨酸尿症和骨质疏松症之间 的相关性以及绝经后妇女中同型半胱氨酸浓度的增加,一些 作者暗示同型半胱氨酸水平升高导致绝经后骨质疏松症。 Framingham825名男性和1174名女性的研究,从59岁到91岁 不等,通过评估1619年间血浆同型半胱氨酸水平和髋部骨 折的相对事件来肯定这一怀疑。 平均血浆总同型半胱氨酸浓 度 为 13.4±9.1μmol/ L , 男 性 为 41 髋 骨 折 , 女 性 为 12.1±5.3μmol/ L,髋部骨折为146。 结果显示,血浆同型半 胱氨酸最高四分位数的男性和女性髋部骨折的风险均高于最 低四分位数,男性和男性的风险几乎是男性的4倍,女性的风 险是1.9倍。150 )因为众所周知身体活动会降低同型半胱氨 酸,以及防止跌倒,因此它可能会影响同型半胱氨酸水平与 骨折风险之间的关联。15因此,开始运动以及适当的补充疗法 似乎是明智的。适用于高同型半胱氨酸和骨质减少/骨质疏松 症的女性和男性。
Autism 自闭症
Children with autism have higher levels of urinary homocysteine than children without autism, which may reflect nutritional defi-ciencies of folic acid, vitamin B6, and vitamin B12.151
自闭症儿童的尿同型半胱氨酸水平高于没有自闭症的儿童,这可 能反映了叶酸,维生素B6和维生素B12的营养缺乏。151
In addition, autistic children have elevated levels of S-adenosylhomocysteine (SAH) and adenosine, whereas levels of methionine, S-adenosylmethionine (SAM), and the SAM/SAH ratio are significantly decreased compared with age-matched controls.152
此外,与年龄匹配的对照组相比,自闭症儿童的 SadenosylhomocysteineSAH)和腺苷水平升高,而蛋氨酸,
S-腺苷甲硫氨酸(SAM)和SAM / SAH比例显着降低152
Drug-Induced Hyperhomocysteinemia 药物诱导的高同型半胱氨酸血症
Because fibrate drugs are known to increase homocysteine levels (see Pharmaceutic Drug Effects on Homocysteine), one random-ized, double-blind crossover study investigated the effect of using fenofibrate adjunctively with 650 mcg of folic acid, 5 mg of vita-min B6, and 50 mcg of vitamin B12, or just fenofibrate in hyperlip-idemic men. Subjects who received the fenofibrate plus placebo had an average increase in homocysteine concentration of 44%. Subsequent to the fenofibrate plus vitamin treatment, it was 13%. In this study, vitamins significantly prevented most of the homo-cysteine increase seen after fenofibrate plus placebo. The authors of this study suggested that routine use of these nutrients might be beneficial with this pharmaceutic therapy.35
因为已知贝特类药物会增加同型半胱氨酸水平(参见“制药药物 对同型半胱氨酸的影响”),一项随机,双盲交叉研究调查了使 用非诺贝特辅助650 mcg叶酸,5 mg维生素B6的效果和50 mcg维生 素B12,或高脂血症男性中的非诺贝特。 接受非诺贝特加安慰剂 的受试者的同型半胱氨酸浓度平均增加44%。 非诺贝特加维生 素治疗后,为13%。在这项研究中,维生素显着阻止了大多数同源非诺贝特加安慰剂后可见半胱氨酸增加。 作者这项研究表明,这种营养素的常规使用可能对这种药物治疗有益。
Many studies cited herein have used a reference range, with 12 to 16 μmol/L being the upper limit of normal for homocysteine. Researchers found a highly significant increase in relative risk of atherosclerotic cardiovascular disease and other disease processes as homocysteine levels increased, even within the normalrange. Optimal levels of homocysteine and vitamin B12 are needed to maintain the methylation cycle, along with adequate levels of vitamin B6 to convert to cysteine, which is a precursor to form GSH. A number of clinical laboratories currently per-form plasma homocysteine determinations, by themselves or within a cardiovascular panel.
本文引用的许多研究使用参考范围,1216μmol/ L是同型半胱 氨酸的正常上限。 研究人员发现,随着同型半胱氨酸水平的增 加,即使在“正常”范围内,动脉粥样硬化性心血管疾病和其他疾 病过程的相对风险也会显着增加。 需要最佳水平的高半胱氨酸 和维生素B12来维持甲基化周期,以及足够水平的维生素B6转化为 半胱氨酸,半胱氨酸是形成GSH的前体。 许多临床实验室目前或 在心血管小组内进行血浆同型半胱氨酸测定。
Although folic acid supplementation (400 mcg/day) alone can reduce homocysteine levels in many subjects, given the impor-tance of vitamins B12 and B6 to proper homocysteine metabo-lism, all three should be used together. In one study, the prevalence of suboptimal levels of these nutrients in men with elevated homocysteine levels was 56.8%, 59.1%, and 25% for folic acid, vitamin B12, and vitamin B6, respectively, indicating that folic acid supplementation alone would not lower homocys-teine levels in many cases.153 In other words, folic acid supple-mentation will only lower homocysteine levels if there are adequate levels of vitamin B12 and B6. This fact could reduce the effect of folic acid fortification of food. In 1998, the Food and Drug Administration mandated the fortification of food prod-ucts with folic acid. Although homocysteine levels have decreased modestly after the fortification of food with folic acid, the effect on mortality has been minor at best.22 This indicates the impor-tance of more aggressive supplementary measures to reduce homocysteine-associated cardiovascular risk. In one study of 100 men with hyperhomocysteinemia, oral therapy with 650 mcg folic acid, 400 mcg vitamin B12, 10 mg vitamin B6, or a combi-nation of the three nutrients was given daily for 6 weeks. Plasma homocysteine was reduced 41.7% during folate therapy and 14.8% during vitamin B12 therapy, whereas 10 mg of vitamin B6 did not reduce plasma homocysteine significantly. The combi-nation worked synergistically to reduce homocysteine levels by 49.8%.154
虽然单独补充叶酸(400 mcg /天)会降低许多受试者的同型半胱氨酸水平,但考虑到维生素B12B6对正常的高半胱氨酸代谢的重要性,所有这三者应该一起使用。 在一项研究中,同型半胱氨酸水平升高的男性中这些营养素的次优水平的患病率分别为叶酸,维生素B12和维生素B656.8%,59.1%和25%,表明叶酸在许多情况下,单独补充酸不会降低同型半胱氨酸水平。153换句话说,如果有足够水平的维生素B12B6,叶酸补充剂只会降低同型半胱氨酸水平。 这一事实可以减少叶酸强化食物的效果。 1998年,美国食品和药物管理局要求用叶酸强化食品。 虽然用叶酸强化食物后同型半胱氨酸水平略有下降,但对死亡率的影响最小。22这表明更积极的补充措施对降低同型半胱氨酸相关心血 管风险的重要性。 在一项针对100名患有高同型半胱氨酸血症的 男性的研究中,每天给予口服治疗650 mcg叶酸,400 mcg维生素 B1210 mg维生素B6或三种营养素的组合,持续6周。 叶酸治疗期 间血浆同型半胱氨酸降低41.7%,维生素B12治疗期间降低14.8%,而10mg维生素B6未显着降低血浆同型半胱氨酸。 该组合协同作 用使同型半胱氨酸水平降低49.8%。154
Several studies using folic acid, vitamin B6, vitamin B12, and betaine, either alone or in combination, demonstrated the ability of these nutrients to normalize homocysteine levels.* Other stud-ies confirmed that oral folate supplementation alone would almost always lower high homocysteine, whereas B6 and B12 would lower homocysteine only in those with a genetic metabolic defect or dietary deficiency in those nutrients, or both.155,156 Some studies used high-dosage oral folate therapy (2.5 to 5 mg) to effectively reduce hyperhomocysteinemia in patients with peripheral athero-sclerotic vascular disease, 50% of whom had abnormally high fast-ing plasma homocysteine levels, whereas 100% had abnormal plasma homocysteine after a methionine load.
一些使用叶酸,维生素B6,维生素B12和甜菜碱(单独或组 合)的研究证明了这些营养素能够使同型半胱氨酸水平正常 化。*其他研究证实,单独口服叶酸补充剂几乎总是如此较低 的高同型半胱氨酸,而B6B12只会降低那些具有遗传代谢缺 陷或膳食缺乏的营养素或两者兼有的同型半胱氨酸。155,156一 些研究使用高剂量口服叶酸治疗(2.55 mg)有效降低外周 动脉粥样硬化血管疾病患者的高同型半胱氨酸血症,其中50%的患者空腹血浆同型半胱氨酸水平异常高,而100%的患者在 蛋氨酸负荷后血浆同型半胱氨酸异常。
Despite the demonstrated efficacy of individual studies lower-ing homocysteine levels with folic acid and B vitamins, a meta-analysis of eight randomized trials of folic acid and vitamin B supplementation to lower homocysteine levels was found to have no significant effects within 5 years on cardiovascular events, cancer, or mortality.157
尽管个体研究证实了降低同型半胱氨酸水平与叶酸和B族维生 素的效果,但对叶酸和维生素B补充降低同型半胱氨酸水平的8项 随机试验的荟萃分析发现5年内对心血管事件,癌症或死亡率无显着影响。157
If a dietary deficiency or an increased demand resulting from genetic biochemical individuality exists for 5-methyl-THF, methylcobalamin, P5P, or betaine, treatment with these active forms of micronutrients should reduce homocysteine levels better than the nonactive forms (e.g., folic acid, cyano-cobalamin, pyridoxine, betaine hydrochloride). In addition, betaine is important when there is a deficiency of the P5P-dependent enzyme cystathionine synthasethe most common genetic abnormality affecting the transsulfuration pathway of homocysteine breakdown. Betaine supplementation in combi-nation with vitamin B6 corrects the hyperhomocysteinemia in these individuals.28,155
如果对于5-甲基-THF,甲基钴胺素,P5P或甜菜碱存在膳食缺乏或由遗传生化个性引起的需求增加,用这些活性形式的 微量营养素治疗应该比非活性形式(例如,叶酸,氰钴胺素) 更好地降低同型半胱氨酸水平。吡哆醇,盐酸甜菜碱)。 此外,当缺乏P5P依赖性酶胱硫醚合酶时,甜菜碱是重要的 -这是影响同型半胱氨酸分解的转硫途径的最常见的遗传异常。 甜菜碱补充剂与维生素B6联合可纠正这些个体的高同型半胱氨酸血症。28,155
Therapeutic Approach 治疗方法
Supplements 补充剂
Folic acid: 800 mcg/day
Vitamin B12: 800 mcg/day
Pyridoxine: 25 to 50 mg/day
If unresponsive to the previous dosages, patients may take the following:
Folinic acid: 800 mcg/day
Methylcobalamin: 800 mcg/day
P5P: 20 mg/day
Betaine (trimethylglycine): 1200 mg/day
NAC: 500 mg/day
5-MethylTHF: 1 to 5 mg/day
如果对先前的剂量没有反应,患者可能会采取以下措施: •亚叶酸:800微克/
Methylcobalamin800 mcg /
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