title: Relationship between S-adenosylmethionine, S-adenosylhomocysteine, asymmetric dimethylarginine, and endothelial function in healthy human subjects during experimental hyper- and hypohomocysteinemia.
abstract: Experimental hyperhomocysteinemia after an oral methionine or homocysteine load is associated with impaired nitric oxide-dependent vasodilatation in healthy human beings. However, it remains unproven that this effect is mediated by elevations in plasma homocysteine. There is evidence that an increase in plasma homocysteine may increase the formation of asymmetric dimethylarginine (ADMA), an inhibitor of nitric oxide synthase. The methyl groups within ADMA are derived from the conversion of S -adenosylmethionine to S -adenosylhomocysteine intermediates in the methionine/homocysteine pathway. No previous study has assessed the role of methylation status, its impact on ADMA formation, and their association with endothelial function in healthy human beings. In a randomized, placebo-controlled, crossover study, 10 healthy subjects (mean age, 29.1 +/- 3.9 years) were administered an oral dose of methionine (0.1 g/kg), l -homocysteine (0.01 g/kg), N-acetylcysteine (NAC) (0.1 g/kg), or placebo. Endothelial function as assessed by flow-mediated dilatation (FMD) of the brachial artery was impaired after both the methionine and homocysteine load compared with placebo at 4 hours (36 +/- 15, 67 +/- 23 vs 219 +/- 26 microm, respectively, P < .001). N-Acetylcysteine had no effect on flow-mediated dilatation. Plasma total homocysteine was significantly elevated at 4 hours after methionine (23.1 +/- 6.2) and homocysteine (41.5 +/- 8.9) loading, but significantly reduced after NAC 2.4 +/- 0.6 vs 7.1 +/- 2.1 micromol/L in the placebo (P < .001). Plasma S-adenosylmethionine/S-adenosylhomocysteine ratio was significantly (P < .001) increased at 4 hours after methionine (10.9 +/- 0.7) compared with homocysteine (5.4 +/- 0.4), NAC (5.0 +/- 0.3), and placebo (6.0 +/- 0.5). Plasma ADMA concentrations were not altered by any intervention. Our results suggest that endothelial dysfunction due to methionine or homocysteine loading is not associated with an increase in plasma ADMA or a disruption in methylation status.
authors.affiliation: Cardiovascular Sciences Research Group, Wales Heart Research Institute, University of Wales College of Medicine, Heath Park CF14 4XN Cardiff, UK.
authors.forename: Sagar
authors.initials: S
authors.lastname: Doshi
authors.forename: Ian
authors.initials: I
authors.lastname: McDowell
authors.forename: Jonathan
authors.initials: J
authors.lastname: Goodfellow
authors.forename: Sally
authors.initials: S
authors.lastname: Stabler
authors.forename: Rainer
authors.initials: R
authors.lastname: Boger
authors.forename: Robert
authors.initials: R
authors.lastname: Allen
authors.forename: Robert
authors.initials: R
authors.lastname: Newcombe
authors.forename: Malcolm
authors.initials: M
authors.lastname: Lewis
authors.forename: Stuart
authors.initials: S
authors.lastname: Moat
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage; D000328:Adult; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood*; D001783:Blood Flow Velocity; D001916:Brachial Artery; D018592:Cross-Over Studies; D003540:Cystathionine / Q000097:blood; D003545:Cysteine / Q000097:blood; D004151:Dipeptides / Q000097:blood; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D006710:Homocysteine / Q000008:administration & dosage / Q000097:blood*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood*; D007700:Kinetics; D008297:Male; D008715:Methionine / Q000008:administration & dosage / Q000097:blood; D010919:Placebos; D012435:S-Adenosylhomocysteine / Q000097:blood*; D012436:S-Adenosylmethionine / Q000097:blood*; D014664:Vasodilation
chemical_list: D004151:Dipeptides; D010919:Placebos; C487735:dimethylarginine; D006710:Homocysteine; D003540:Cystathionine; C028505:cysteinylglycine; D012436:S-Adenosylmethionine; D001120:Arginine; D012435:S-Adenosylhomocysteine; D008715:Methionine; D003545:Cysteine; D000111:Acetylcysteine