Transsulfuration pathway thiols and methylated arginines: the Hunter Community Study.
BACKGROUND
Serum homocysteine, when studied singly, has been reported to be positively associated both with the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine [ADMA, via inhibition of dimethylarginine dimethylaminohydrolase (DDAH) activity] and with symmetric dimethylarginine (SDMA). We investigated combined associations between transsulfuration pathway thiols, including homocysteine, and serum ADMA and SDMA concentrations at population level.


METHODS
Data on clinical and demographic characteristics, medication exposure, C-reactive protein, serum ADMA and SDMA (LC-MS/MS), and thiols (homocysteine, cysteine, taurine, glutamylcysteine, total glutathione, and cysteinylglycine; capillary electrophoresis) were collected from a sample of the Hunter Community Study on human ageing [n = 498, median age (IQR) = 64 (60-70) years].


RESULTS
REGRESSION ANALYSIS SHOWED THAT: a) age (P = 0.001), gender (P = 0.03), lower estimated glomerular filtration rate (eGFR, P = 0.08), body mass index (P = 0.008), treatment with beta-blockers (P = 0.03), homocysteine (P = 0.02), and glutamylcysteine (P = 0.003) were independently associated with higher ADMA concentrations; and b) age (P = 0.001), absence of diabetes (P = 0.001), lower body mass index (P = 0.01), lower eGFR (P<0.001), cysteine (P = 0.007), and glutamylcysteine (P < 0.001) were independently associated with higher SDMA concentrations. No significant associations were observed between methylated arginines and either glutathione or taurine concentrations.


CONCLUSIONS
After adjusting for clinical, demographic, biochemical, and pharmacological confounders the combined assessment of transsulfuration pathway thiols shows that glutamylcysteine has the strongest and positive independent associations with ADMA and SDMA. Whether this reflects a direct effect of glutamylcysteine on DDAH activity (for ADMA) and/or cationic amino acid transport requires further investigations.
Division of Applied Medicine, University of Aberdeen, Aberdeen, United Kingdom. a.a.mangoni@abdn.ac.uk
Arduino A
AA
Mangoni
Angelo
A
Zinellu
Ciriaco
C
Carru
John R
JR
Attia
Mark
M
McEvoy
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000097:blood*; D000581:Amidohydrolases / Q000097:blood*; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D001315:Australia; D002097:C-Reactive Protein / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000097:blood / Q000517:prevention & control; D015331:Cohort Studies; D003154:Community Medicine; D003545:Cysteine / Q000031:analogs & derivatives / Q000097:blood; D004151:Dipeptides / Q000097:blood; D005260:Female; D005978:Glutathione / Q000097:blood; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D013654:Taurine / Q000097:blood
D000319:Adrenergic beta-Antagonists; D004151:Dipeptides; D006710:Homocysteine; D013654:Taurine; C028505:cysteinylglycine; C024917:symmetric dimethylarginine; C018524:N,N-dimethylarginine; D002097:C-Reactive Protein; D001120:Arginine; D000581:Amidohydrolases; C059999:dimethylargininase; D005978:Glutathione; D003545:Cysteine