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.