Regulation of biosynthesis of guanidinosuccinic acid in isolated rat hepatocytes and in vivo.
To clarify the metabolic pathway of guanidinosuccinic acid (GSA), we investigated the relationship between GSA synthesis and the urea cycle. In isolated rat hepatocytes, GSA formation increased as urea concentration was raised; the effect of urea was not modified by the addition of ammonium chloride. Other urea cycle intermediates, including arginine and cyanate, a degradation product of urea, failed to stimulate GSA synthesis. Ornithine and arginine, which stimulate urea synthesis, strongly inhibited urea-stimulated GSA synthesis in the presence of 10 mM ammonium chloride, but the inhibitory effect of ornithine was not observed when ammonium chloride was not present. Citrulline (5 mM) strongly inhibited urea-stimulated GSA synthesis with or without ammonium chloride. D,L-norvaline, which inhibits urea cycle enzymes, strongly inhibited GSA synthesis. Following urea injection, hepatic GSA levels also increased in vivo, but there was little change in hepatic arginine. However, the addition of ornithine or D,L-norvaline inhibited the production of hepatic GSA, although arginine was increased substantially. These results indicate that GSA synthesis occurs in rat hepatocytes and is stimulated by urea. The data also suggest that the urea cycle enzymes catalyze some of the biochemical reactions in the GSA synthetic pathway.
D000596:Amino Acids / Q000378:metabolism; D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D002956:Citrulline / Q000494:pharmacology; D006146:Guanidines / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D066298:In Vitro Techniques; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D009952:Ornithine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013386:Succinates / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D014508:Urea / Q000096:biosynthesis / Q000494:pharmacology; D014633:Valine / Q000494:pharmacology / Q000031:analogs & derivatives
D000596:Amino Acids; D006146:Guanidines; D013386:Succinates; D000643:Ammonium Chloride; D002956:Citrulline; C001318:guanidinosuccinic acid; D014508:Urea; D001120:Arginine; C005313:norvaline; D009952:Ornithine; D014633:Valine