Inhibition of N-methyl-N'-nitro-N-nitrosoguanidine-activated guanylate cyclase by anticarcinogenic agents.
Recent studies have demonstrated that nitroso chemical carcinogens markedly activate guanylate cyclase, which catalyzes the production of guanosine 3',5'-monophosphate (cyclic GMP). We therefore examined the effect of inhibitors of carcinogenic compounds on guanylate cyclase activation by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). An antioxidant group of anticarcinogenic compounds was effective. Disulfiram and phenethyl isothiocyanate exhibited the most potent inhibition. Inhibitor constants (Ki) for disulfiram and phenethyl isothiocyanate were 1.2 x 10(-5) M and 4.9 x 10(-5) M, respectively. Sodium diethyldithiocarbamate, phenyl isothiocyanate, butylated hydroxyanisole and ethoxyquin showed moderate inhibitory effects. Sodium selenide decreased the MNNG-activated guanylate cyclase activity to about 30%, and it was inhibitory at the low concentration of 10(-5) M. The present data suggest that one of the mechanisms by which anticarcinogenic compounds exert their effect may in part be related to the inhibition of guanylate cyclase.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology; D004221:Disulfiram / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism*; D006454:Hemoglobins; D008297:Male; D008769:Methylnitronitrosoguanidine / Q000037:antagonists & inhibitors*; D051379:Mice; D012643:Selenium / Q000494:pharmacology; D013861:Thiocyanates / Q000494:pharmacology
D000970:Antineoplastic Agents; D002219:Carbamates; D006454:Hemoglobins; D013861:Thiocyanates; D008769:Methylnitronitrosoguanidine; D006162:Guanylate Cyclase; D012643:Selenium; D004221:Disulfiram