Interrelations Between Plasma Homocysteine and Intracellular S-Adenosylhomocysteine

Fu, Weiyu; Dudman, Nicholas P.B.; Perry, Michael A.; Young, Kenny; Wang, Xing Li

doi:10.1006/bbrc.2000.2587

Cited by 46 publications

(36 citation statements)

References 22 publications

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“…In agreement with previous reports, plasma concentrations of AdoHcy were markedly increased in our patients with chronic HHcy (14,26,39 ). In erythrocytes, however, a transient increase in plasma tHcy after methionine loading in humans did not lead to increases in AdoHcy or AdoMet (39 ).…”

Section: Discussionsupporting

confidence: 93%

Disturbed Homocysteine and Methionine Cycle Intermediates S-Adenosylhomocysteine and S-Adenosylmethionine Are Related to Degree of Renal Insufficiency in Type 2 Diabetes

et al. 2005

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Section: Discussionsupporting

confidence: 93%

Disturbed Homocysteine and Methionine Cycle Intermediates S-Adenosylhomocysteine and S-Adenosylmethionine Are Related to Degree of Renal Insufficiency in Type 2 Diabetes

et al. 2005

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“…SAH levels: Hepatocyte pellets were homogenized in 0.5 mol/L HClO 4 , and the filtered acid extracts directly subjected to HPLC analysis for the determination of hepatocellular SAH levels following the procedure of Fu et al [38] as detailed in our publication [22].…”

Section: Hepatocyte Isolation and Experimental Designmentioning

confidence: 99%

Role of elevated S-adenosylhomocysteine in rat hepatocyte apoptosis: Protection by betaine

Kharbanda

Rogers²,

Mailliard

et al. 2005

Biochemical Pharmacology

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Previous studies from our laboratory have shown that ethanol consumption results in an increase in hepatocellular S-adenosylhomocysteine levels. Because S-adenosylhomocysteine is a potent inhibitor of methylation reactions, we propose that increased intracellular S-adenosylhomocysteine levels could be a major contributor to ethanol-induced pathologies. To test this hypothesis, hepatocytes isolated from rat livers were grown on collagen-coated plates in Williams' medium E containing 5% FCS and exposed to varying concentrations of adenosine in order to increase intracellular S-adenosylhomocysteine levels. We observed increases in caspase-3 activity following exposure to adenosine. This increase in caspase activity correlated with increases in intracellular S-adenosylhomocysteine levels and DNA hypoploidy. The adenosine-induced changes could be significantly attenuated by betaine administration. The mechanism of betaine action appeared to be via the methylation reaction catalyzed by betaine-homocysteine-methyltransferase. To conclude, our results indicate that the elevation of S-adenosylhomocysteine levels in the liver by ethanol is a major factor in altering methylation reactions and in increasing apoptosis in the liver. We conclude that ethanol-induced alteration in methionine metabolic pathways may play a crucial role in the pathologies associated with alcoholic liver injury and that betaine administration may have beneficial therapeutic effects. Published by Elsevier Inc.

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“…Indeed, recent data suggest that a chronic elevation of homocysteine level might indirectly reduce methylation of DNA, RNA, proteins, and phospholipids through a concomitant increase in SAH level secondary to homocysteine-mediated reversal of the SAH hydrolase reaction . High plasma levels were effectively associated with increased plasma and lymphocyte SAH and a decreased SAM to SAH ratio that could negatively affect cellular methylation potential (Fu et al, 2000;Melnyk et al, 2000;Yi et al, 2000). Therefore, further investigations are needed to assess potential vascular effects of hyperhomocysteinemiaassociated changes in the SAM to SAH ratio, which regulates SAM-dependent methyltransferases and hence, methylation reactions.…”

Section: Durand Et Almentioning

confidence: 99%

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Durand

Prost²,

Loreau

et al. 2001

Laboratory Investigation

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SUMMARY:Based on recent retrospective, prospective, and experimental studies, mild to moderate elevation of fasting or postmethionine-load plasma homocysteine is accepted as an independent risk factor for cardiovascular disease and thrombosis in both men and women. Hyperhomocysteinemia results from an inhibition of the remethylation pathway or from an inhibition or a saturation of the transsulfuration pathway of homocysteine metabolism. The involvement of a high dietary intake of methionine-rich animal proteins has not yet been investigated and cannot be ruled out. However, folate deficiency, either associated or not associated with the thermolabile mutation of the N 5,10 -methylenetetrahydrofolate reductase, and vitamin B 6 deficiency, perhaps associated with cystathionine ␤-synthase defects or with methionine excess, are believed to be major determinants of the increased risk of cardiovascular disease related to hyperhomocysteinemia. Recent experimental studies have suggested that moderately elevated homocysteine levels are a causal risk factor for atherothrombotic disease because they affect both the vascular wall structure and the blood coagulation system. The oxidant stress that results from impaired homocysteine metabolism, which modifies the intracellular redox status, might play a central role in the molecular mechanisms underlying moderate hyperhomocysteinemia-mediated vascular disorders. Because folate supplementation can efficiently reduce plasma homocysteine levels, both in the fasting state and after methionine loading, results from further prospective cohort studies and from on-going interventional trials will determine whether homocysteine-lowering therapies can contribute to the prevention and reduction of cardiovascular risk. Additionally, these studies will provide unequivocal arguments for the independent and causal relationship between hyperhomocysteinemia and atherothrombotic disease. (Lab Invest 2001, 81:645-672).C ardiovascular diseases remain the leading cause of mortality in Western populations. Hyperlipoproteinemia, hypertension, diabetes, obesity, and tobacco smoking are the main risk factors for atherosclerosis and its thrombotic complications. However, these factors alone cannot account for all of the deaths caused by vascular pathologies.As early as 1969, clinical studies conducted in homocystinuric children revealed the importance of severe hyperhomocysteinemia in premature development of atherosclerosis and thromboembolism (McCully, 1983). According to numerous retrospective case-controlled studies, moderate increases in plasma homocysteine, which can be precisely quantitated by high performance liquid chromatography (HPLC), raise the risk for cardiovascular disease 2-fold, after adjusting for classic risk factors. Moreover, up to 20% to 40% of patients with vascular pathologies present moderate to intermediate hyperhomocysteinemia. However, results from prospective studies are inconsistent. Additionally, molecular mechanisms underlying hyperhomocysteinemia-induced vascular diseas...

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Interrelations Between Plasma Homocysteine and Intracellular S-Adenosylhomocysteine

Cited by 46 publications

References 22 publications

Disturbed Homocysteine and Methionine Cycle Intermediates S-Adenosylhomocysteine and S-Adenosylmethionine Are Related to Degree of Renal Insufficiency in Type 2 Diabetes

Disturbed Homocysteine and Methionine Cycle Intermediates S-Adenosylhomocysteine and S-Adenosylmethionine Are Related to Degree of Renal Insufficiency in Type 2 Diabetes

Role of elevated S-adenosylhomocysteine in rat hepatocyte apoptosis: Protection by betaine

Impaired Homocysteine Metabolism and Atherothrombotic Disease

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