Methyl group deficiency and guanidino production in uremia.
Guanidinosuccinic acid (GSA) is one of the earliest uremic toxins isolated and its toxicity identified. Its metabolic origins have remained obscure until recently when a series of studies showed that it arose from the oxidation of argininosuccinic acid (ASA) by free radicals. The stimulus for this oxidation, occurring optimally in the presence of the failed kidney, is the rising level of urea which, through enzyme inhibition, results in a decline in hepatic levels of the semi-essential amino acid, arginine. It is further noted that concentrations of GSA in both serum and urine decline sharply in animals and humans exposed to the essential amino acid, methionine. In this review the argument is advanced that uremics suffer from a defective ability to generate methyl groups due to anorexia, dietary restrictions and renal protein leakage. This leads to the accumulation of homocysteine, a substance known to produce vascular damage. Even in healthy subjects intake of choline together with methionine is insufficient to satisfy total metabolic requirements for methyl groups. In end-stage renal disease, therefore, protein restriction contributes to the build-up of toxins in uremia. Replacement using specific amino acid mixtures should be directed toward identified deficiencies and adequacy monitored by following serum levels of the related toxins, in this case GSA and homocysteine.
Cohen
Burton D
BD
Albert Einstein College of Medicine, Bronx, NY, USA. burt1071@aol.com
D000818:Animals; D001120:Arginine / Q000737:chemistry / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D006146:Guanidines / Q000378:metabolism*; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008715:Methionine / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D008956:Models, Chemical; D010100:Oxygen / Q000378:metabolism; D013386:Succinates / Q000378:metabolism*; D013997:Time Factors; D000637:Transaminases / Q000378:metabolism; D014511:Uremia / Q000378:metabolism
D005609:Free Radicals; D006146:Guanidines; D013386:Succinates; D006710:Homocysteine; C001318:guanidinosuccinic acid; D001120:Arginine; D008715:Methionine; D000637:Transaminases; D010100:Oxygen