亚甲基四氢叶酸还原酶及甲硫氨酸合成酶基因多态性与男性不育

易感基因、环境及营养等因素在疾病发生过程中起到了重要作用.亚甲基四氢叶酸还原酶(MTHFR)、甲硫氨酸合成酶(MS)是叶酸和同型半胱氨酸(Hcy)代谢中的重要酶,其活性缺陷可能引起体内高同型半胱氨酸血症和DNA甲基化异常而导致多种疾病.目前对MTHFR基因单核苷酸多态性C677T与男性不育的相关性报道结论不一,而对另两...     

心理应激对大鼠叶酸和同型半胱氨酸的影响及补充叶酸的调节作用

目的明确应激状态下机体血浆和脑脊液中同型半胱氨酸(Hcy)浓度及组织叶酸含量的变化,探讨叶酸在应激状态下对Hcy水平的调节作用。方法以束缚作为应激原建立大鼠心理应激模型,动物分为对照组、束缚3w组,束缚3w同时补充叶酸组。认识心理应激对机体Hcy和叶酸水平的影响,及应激状态下补充叶酸对机体Hcy水平的调节作用。结果心理应激动物叶酸代谢发生了显著的变化,血浆叶酸水平显著低于对照组,小肠粘膜上皮、肝脏、皮层和海马组织中叶酸的含量也明显降低。补充叶酸可以显著升高心理应激后机体的叶酸水平,降低心理应激所致的血浆同型半胱氨酸水平升高。结论应激状态下机体叶酸含量的降低可能是同型半胱氨酸水平升高的重要原因之一。     

亚甲基四氢叶酸还原酶基因多态性与母儿结局

亚甲基四氢叶酸还原酶基因677C→T突变是引起亚甲基四氢叶酸还原酶活性降低、高同型半胱氨酸血症、高危妊娠和胎儿畸形的重要遗传学因素。该文就近年来亚甲基四氢叶酸还原酶基因多态性与高危妊娠和胎儿畸形关系做一简要综述。     

亚甲基四氢叶酸还原酶基因多态性与母儿结局

亚甲基四氢叶酸还原酶基因 6 77C→T突变是引起亚甲基四氢叶酸还原酶活性降低、高同型半胱氨酸血症、高危妊娠和胎儿畸形的重要遗传学因素。该文就近年来亚甲基四氢叶酸还原酶基因多态性与高危妊娠和胎儿畸形关系做一简要综述。     

叶酸、同型半胱氨酸及MTHFR C677T基因多态性与肾功能的关系

同型半胱氨酸是蛋氨酸代谢生成的一种含硫氨基酸,也是反应性血管损伤氨基酸,代谢紊乱可形成高同型半胱氨酸血症。叶酸又名维生素B9,是人体必需的一种微量营养素,缺乏可导致高同型半胱氨酸水平。亚甲基四氢叶酸还原酶(MTHFR)是叶酸和同型半胱氨酸代谢途径中的一个关键酶,MTHFR 677 C-T的突变致酶的活性和耐热性下降导致同型半胱氨酸升高,高同型半胱氨酸血症可引起血栓性疾病和动脉粥样硬化,近年来发现这也是影响肾功能的一个新的独立危险因素。本文对叶酸、血浆Hcy水平和MTHFR C677T基因多态性与肾功能损伤关系进行概述。     

甜菜碱的甲基供体作用及防治脂肪肝的研究进展

甜菜碱是一种广泛存在于动植物体内的多甲基供体。它参与同型半胱氨酸的再甲基化,从而降低血浆同型半胱氨酸水平。甜菜碱也可调节脂肪代谢,减少肝脏脂肪沉积,因此能有效防治脂肪肝。其作用机制是抑制脂肪的合成,促进肝脏脂肪的输出。本文主要综述了甜菜碱作为甲基供体在机体甲基化反应中所起的作用以及其防治脂肪肝的研究进展。     

072 甜菜碱的甲基供体作用及防治脂肪肝的研究进展

甜菜碱是一种广泛存在于动植物体内的多甲基供体.它参与同型半胱氨酸的再甲基化,从而降低血浆同型半胱氨酸水平.甜菜碱也可调节脂肪代谢,减少肝脏脂肪沉积,因此能有效防治脂肪肝.其作用机制是抑制脂肪的合成,促进肝脏脂肪的输出.本文主要综述了甜菜碱作为甲基供体在机体甲基化反应中所起的作用以及其防治脂肪肝的研究进展.     

亚甲基四氢叶酸还原酶基因多态性与出生缺陷

亚甲基四氢叶酸还原酶(MTHFR)基因多态性特别是677C→T突变可导致MTHFR酶活性下降，进一步造成叶酸代谢障碍和血浆同型半胱氨酸增高，被认为是引起神经管缺陷(NTD)、Down综合征、唇腭裂等多种出生缺陷的高危遗传因素，妊娠前及妊娠期补充叶酸是预防上述出生缺陷发生的有效措施。     

同型半胱氨酸血症与临床

正同型半胱氨酸(Hcy)是非蛋白质成分,是一种含硫的氨基酸,全部的细胞都可产生Hcy在细胞内由甲硫氨酸去甲基后形成。血浆Hcy水平与血浆叶酸和维生素B12呈负相关,与维生素B6略呈负相关。如果参与Hcy代谢的酶及辅助因子缺陷,则导致细胞内Hcy的代谢受阻;或组织器官对其清除不足,均可导致高Hcy血症~([1、2])。1高同型半胱氨酸血症与临床疾病1.1高同型半胱氨酸血症与慢性肾脏病。叶承良等~([2])观察了223例     

亚甲基四氢叶酸还原酶与出血缺陷疾病

5，10－亚甲基四氢叶酸还原酶基因多态性是导致叶酸代谢障碍及高同型半胱氨酸血症的遗传性因素，与胎儿出生缺陷和心血管疾病有密切的关系。该文阐述了亚甲基四氢叶酸还原酶的生物学特性，基因多态性及其与出生缺陷的关系。为神经管缺陷，反复流产等疾病的发生机制及治疗措施提供一定的理论依据。     

Effect of vitamin B12-deficiency on the activity of hepatic cystathionine beta-synthase in rats

The effect of vitamin B12(B12)-deficiency on the activities of hepatic methionine synthase, homocysteine methyltransferase, and cystathionine beta-synthase was investigated in rats. The rats bred from B12-deficient dams were fed the B12-deficient diets for 150 days after weaning. Growth retardation of the B12-deficient rats was already observed on day 30 and continued through 150 days. But dietary supplementation of 0.5% DL-methionine slightly improved the growth retardation. Urinary excretion of methylmalonic acid increased to about 15 mg/mg creatinine and hepatic B12 concentration declined to about 2 ng/g liver after a 150-day feeding of the B12-deficient diets. Hepatic methionine synthase activity in rats fed the B12-deficient diets supplemented with or without methionine decreased to about 5% of B12-supplemented controls. Hepatic betaine-homocysteine methyltransferase activity showed no significant change caused by B12-deficiency. Hepatic cystathionine beta-synthase activity in rats fed the B12-deficient diets supplemented with or without methionine decreased to about 61% and 27% of their B12-supplemented controls, respectively, but the decrease was partially improved by methionine supplementation. In conclusion, the rats bred from B12-deficient dams showed a severe B12-deficiency after a 150-day feeding of the B12-deficient diets. The decrease of hepatic cystathionine beta-synthase activity was supposed to be due to the adaptation by the defect of methionine resynthesis.     

Selenium deficiency in Fisher-344 rats decreases plasma and tissue homocysteine concentrations and alters plasma homocysteine and cysteine redox status

The purpose of the present study was to determine the effect of graded amounts of dietary selenium on plasma and tissue parameters of methionine metabolism including homocysteine. Male weanling Fisher-344 rats (n = 7-8/group) were fed a selenium-deficient, torula yeast-based diet, supplemented with 0 (selenium deficient), 0.02, 0.05 or 0.1 microg (adequate) selenium (as selenite)/g diet. After 61 d, plasma total homocysteine and cysteine were decreased (P < 0.0001) and glutathione increased (P < 0.0001) by selenium deficiency. The concentrations of homocysteine in kidney and heart were decreased (P = 0.02) by selenium deficiency. The activities of liver betaine homocysteine methyltransferase, methionine synthase, S-adenosylmethionine synthase, cystathionine synthase and cystathionase were determined; selenium deficiency affected only betaine homocysteine methyltransferase, which was decreased (P < 0.0001). The ratios of plasma free reduced homocysteine (or cysteine) to free oxidized homocysteine (or cysteine) or to total homocysteine (or cysteine) were increased by selenium deficiency, suggesting that selenium status affects the normally tightly controlled redox status of these thiols. Most differences due to dietary selenium were between rats fed 0 or 0.02 microg selenium/g diet and those fed 0.05 or 0.1 microg selenium/g diet. The metabolic consequences of a marked decrease in plasma homocysteine and smaller but significant decreases in tissue homocysteine are not known.     

Type I diabetes leads to tissue-specific DNA hypomethylation in male rats

Numerous perturbations of methyl group and homocysteine metabolism have been documented as an outcome of diabetes. It has also been observed that there is a transition from hypo- to hyperhomocysteinemia in diabetes, often concurrent with the development of nephropathy. The objective of this study was to characterize the temporal changes in methyl group and homocysteine metabolism in the liver and kidney and to determine the impact these alterations have on DNA methylation in type 1 diabetic rats. Male Sprague-Dawley rats were injected with streptozotocin (60 mg/kg body weight) to induce diabetes and samples were collected at 2, 4, and 8 wk. At 8 wk, hepatic and renal betaine-homocysteine S-methyltransferase activities were greater in diabetic rats, whereas methionine synthase activity was lower in diabetic rat liver and kidney did not differ. Cystathionine beta-synthase abundance was greater in the liver but less in the kidney of diabetic rats. Both hepatic and renal glycine N-methyltransferase (GNMT) activity and abundance were greater in diabetic rats; however, changes in renal activity and/or abundance were present only at 2 and 4 wk, whereas hepatic GNMT was induced at all time points. Most importantly, we have shown that genomic DNA was hypomethylated in the liver, but not the kidney, in diabetic rats. These results suggest that diabetes-induced perturbations of methyl group and homocysteine metabolism lead to functional methyl deficiency, resulting in the hypomethylation of DNA in a tissue-specific fashion.     

Betaine lowers elevated s-adenosylhomocysteine levels in hepatocytes from ethanol-fed rats

Previous studies showed that chronic ethanol administration inhibits methionine synthase activity, resulting in impaired homocysteine remethylation to form methionine. This defect in homocysteine remethylation was shown to increase plasma homocysteine and to interfere with the production of hepatic S-adenosylmethionine (SAM) in ethanol-fed rats. These changes were shown to be reversed by the administration of betaine, an alternative methylating agent. This study was undertaken to determine additional effects of ethanol on methionine metabolism and their functional consequences. The influences of methionine loading and betaine supplementation were also evaluated. Adult Wistar rats were fed ethanol or a control Lieber-DeCarli liquid diet for 4 wk, and metabolites of the methionine cycle were measured in vitro in isolated hepatocytes under basal and methionine-supplemented conditions. S-Adenosylhomocysteine (SAH) concentrations were elevated in hepatocytes isolated from ethanol-fed rats compared with controls and in hepatocytes from both groups when supplemented with methionine. The addition of betaine to the methionine-supplemented incubation media reduced the elevated SAH levels. The decrease in the intracellular SAH:SAM ratio due to ethanol consumption inhibited the activity of the liver-specific SAM-dependent methyltransferase, phosphatidylethanolamine methyltransferase. Our data indicate that betaine, by remethylating homocysteine and removing SAH, overcomes the detrimental effects of ethanol consumption on methionine metabolism and may be effective in correcting methylation defects and treating liver diseases.     

Dietary folate and selenium affect dimethylhydrazine-induced aberrant crypt formation,global DNA methylation and one-carbon metabolism in rats

Several observations suggest a role for DNA methylation in cancer pathogenesis. Although both selenium and folate deficiency have been shown to cause global DNA hypomethylation and increased cancer susceptibility, the nutrients have different effects on one-carbon metabolism. Thus, the purpose of this study was to investigate the interactive effects of dietary selenium and folate. Weanling, Fischer-344 rats (n = 23/diet) were fed diets containing 0 or 2.0 mg selenium (as selenite)/kg and 0 or 2.0 mg folate/kg in a 2 x 2 factorial design. After 3 and 4 wk of a 12-wk experiment, 19 rats/diet were injected intraperitoneally with dimethylhydrazine (DMH, 25 mg/kg) and 4 rats/diet were administered saline. Selenium deficiency decreased (P < 0.05) colonic DNA methylation and the activities of liver DNA methyltransferase and betaine homocysteine methyltransferase and increased plasma glutathione concentrations. Folate deficiency increased (P < 0.05) the number of aberrant crypts per aberrant crypt foci, the concentration of colonic S-adenosylhomocysteine and the activity of liver cystathionine synthase. Selenium and folate interacted (P < 0.0001) to influence one-carbon metabolism and cancer susceptibility such that the number of aberrant crypts and the concentrations of plasma homocysteine and liver S-adenosylhomocysteine were the highest and the concentrations of plasma folate and liver S-adenosylmethionine and the activity of liver methionine synthase were the lowest in rats fed folate-deficient diets and supplemental selenium. These results suggest that selenium deprivation ameliorates some of the effects of folate deficiency, probably by shunting the buildup of homocysteine (as a result of folate deficiency) to glutathione.     

Methionine synthase D919G polymorphism is a significant but modest determinant of circulating homocysteine concentrations.

Elevation in plasma homocysteine concentration has been associated with vascular disease and neural tube defects. Methionine synthase is a vitamin B(12)-dependent enzyme that catalyses the remethylation of homocysteine to methionine. Therefore, defects in this enzyme may result in elevated homocysteine levels. One relatively common polymorphism in the methionine synthase gene (D919G) is an A to G transition at bp 2,756, which converts an aspartic acid residue believed to be part of a helix involved in co-factor binding to a glycine. We have investigated the effect of this polymorphism on plasma homocysteine levels in a working male population (n = 607) in which we previously described the relationship of the C677T "thermolabile" methylenetetrahydrofolate reductase (MTHFR) polymorphism with homocysteine levels. We found that the methionine synthase D919G polymorphism is significantly (P = 0.03) associated with homocysteine concentration, and the DD genotype contributes to a moderate increase in homocysteine levels across the homocysteine distribution (OR = 1.58, DD genotype in the upper half of the homocysteine distribution, P = 0.006). Unlike thermolabile MTHFR, the homocysteine-elevating effects of the methionine synthase polymorphism are independent of folate and B(12) levels; however, the DD genotype has a larger homocysteine-elevating effect in individuals with low B(6) levels. This polymorphism may, therefore, make a moderate, but significant, contribution to clinical conditions that are associated with elevated homocysteine.     

B-vitamins, homocysteine metabolism and CVD

The present review focuses on the B-vitamins, i.e. folate, vitamin B12, vitamin B6 and riboflavin, that are involved in homocysteine metabolism. Homocysteine is a S-containing amino acid and its plasma concentrations can be raised by various constitutive, genetic and lifestyle factors, by inadequate nutrient status and as a result of systemic disease and various drugs. Hyperhomocysteinaemia is a modest independent predictor of CVD and stroke, but causality and the precise pathophysiological mechanism(s) of homocysteine action remain unproven. The predominant nutritional cause of raised plasma homocysteine in most healthy populations is folate insufficiency. Vitamin B12 and, to a lesser extent, vitamin B6 are also effective at lowering plasma homocysteine, especially after homocysteine lowering by folic acid in those individuals presenting with raised plasma homocysteine. However, riboflavin supplementation appears to be effective at lowering plasma homocysteine only in those individuals homozygous for the T allele of the C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene. This gene codes for the MTHFR enzyme that produces methyltetrahydrofolate, which, in turn, is a substrate for the remethylation of homocysteine by the vitamin B12-dependent enzyme methionine synthase. Individuals with the MTHFR 677TT genotype are genetically predisposed to elevated plasma homocysteine, and in most populations have a markedly higher risk of CVD.     

Polymorphism of genes encoding homocysteine metabolism–related enzymes and risk for cardiovascular disease

The aim of this review is to present a general overview of the relationships among homocysteine metabolism, polymorphism of the genes encoding homocysteine metabolism–related enzymes, and the nutrients influencing the plasma homocysteine level. Combining these factors creates a profile of an individual's susceptibility to complex diseases associated with hyperhomocysteinemia. Homocysteine is an amino acid derived from the demethylation of methionine. Hyperhomocysteinemia is associated with an increased risk of several complex diseases, including cardiovascular diseases. The level of plasma homocysteine depends on the combined effects of genetic and environmental factors. Polymorphisms of genes encoding homocysteine metabolism–related enzymes, such as methylenetetrahydrofolate reductase, methionine synthase, methionine synthase reductase, and cystathionine β-synthase, influence plasma homocysteine concentration and thereby cardiovascular health. On the other hand, homocysteine metabolism may be modulated by dietary intake of the nutrients involved in homocysteine metabolism (ie, folates, vitamin B₆, and vitamin B₁₂). Thus, the appropriate health-promoting doses of these nutrients may vary among certain groups of individuals, depending on their genotypes and other risk factors for complex diseases. Better understanding of the relationship between genotype and nutrition influencing the plasma total homocysteine level and cardiovascular health may improve the cardiovascular diagnostic tests (ie, measurement of biologic markers). It could be possible to define the level of progression, severity, and susceptibility to disease much earlier than it is done now. In conclusion, the introduction of combined dietary and pharmacologic treatment would be possible at the initial stages of disease.     

Cobalt-vitamin B-12 deficiency decreases methionine synthase activity and phospholipid methylation in sheep.

Two groups of lambs were fed either a Co-deficient or a Co-sufficient whole barley-based diet for 28 wk to induce a severe Co-vitamin B-12 deficiency. Holo and apo methionine synthase activities were significantly lower in the liver, kidney and spinal cord of Co-deficient animals compared with controls. Neither form of this enzyme in the brain was affected by Co deficiency. The ratio of the tissue concentrations of S-adenosyl methionine to S-adenosyl homocysteine was significantly lower only in the liver of Co-deficient animals, suggesting that the activity of hepatic SAM-dependent methyltransferase enzymes would be impaired. Measurements of tissue concentrations of phosphatidyl choline and phosphatidyl ethanolamine revealed lower concentrations of phosphatidyl choline and a lower phosphatidyl choline:phosphatidyl ethanolamine ratio in both liver and brain of the Co-deficient animals. The latter finding occurred in the absence of changes in either methionine synthase activity or the methylation ratio and may result from impaired availability of hepatic phosphatidyl choline for transport into the brain.     

Dietary intake of S-(α-carboxybutyl)-dl-homocysteine induces hyperhomocysteinemia in rats

Betaine homocysteine S-methyltransferase (BHMT) catalyzes the transfer of a methyl group from betaine to homocysteine (Hcy), forming dimethylglycine and methionine. We previously showed that inhibiting BHMT in mice by intraperitoneal injection of S-(α-carboxybutyl)-dl-homocysteine (CBHcy) results in hyperhomocysteinemia. In the present study, CBHcy was fed to rats to determine whether it could be absorbed and cause hyperhomocysteinemia as observed in the intraperitoneal administration of the compound in mice. We hypothesized that dietary administered CBHcy will be absorbed and will result in the inhibition of BHMT and cause hyperhomocysteinemia. Rats were meal-fed every 8 hours an l-amino acid–defined diet either containing or devoid of CBHcy (5 mg per meal) for 3 days. The treatment decreased liver BHMT activity by 90% and had no effect on methionine synthase, methylenetetrahydrofolate reductase, phosphatidylethanolamine N-methyltransferase, and CTP:phosphocholine cytidylyltransferase activities. In contrast, cystathionine β-synthase activity and immunodetectable protein decreased (56% and 26%, respectively) and glycine N-methyltransferase activity increased (52%) in CBHcy-treated rats. Liver S-adenosylmethionine levels decreased by 25% in CBHcy-treated rats, and S-adenosylhomocysteine levels did not change. Furthermore, plasma choline decreased (22%) and plasma betaine increased (15-fold) in CBHcy-treated rats. The treatment had no effect on global DNA and CpG island methylation, liver histology, and plasma markers of liver damage. We conclude that CBHcy-mediated BHMT inhibition causes an elevation in total plasma Hcy that is not normalized by the folate-dependent conversion of Hcy to methionine. Furthermore, metabolic changes caused by BHMT inhibition affect cystathionine β-synthase and glycine N-methyltransferase activities, which further deteriorate plasma Hcy levels.