Effect of Polycyclic Hydrocarbons on Steroid 11β-Hydroxylase Activity of the Adrenal in Rats

Summary The effects of 7,12-dimethylbenz(a)anthracene (DMBA), 3-methylcholanthrene (3-MC), and metopirone on 11β-hydroxylase activity in the adrenal has been investigated. When a single dose of 3-MC or metopirone was given in vivo and 11β-hydroxylase activity in the adrenal was measured in vitro , no inhibition of the enzyme activity was observed. Repeated i.p. injections of metopirone to the rats, however, caused a 30 to 40% inhibition of steroid 11β-hydroxylation in the adrenal incubated in vitro . Similar results were obtained with repeated dosages of 3-MC, but to a lesser degree. DMBA, in a single dose of 20 mg given p.o., induced a marked decrease of 11β-hydroxylase activity only in the adrenals which were necrotic. There was no reduction of 11β-hydroxylase activity in adrenals of rats in which the 20 mg dose did not induce necrosis. In vitro incubation of adrenal homogenate in the presence of metopirone caused a marked inhibition of corticosterone production, but there was only a 20% inhibition with 3-MC. Metopirone is a competitive inhibitor, but 3-MC is not. Irradiation of 3-MC under a tungsten lamp for 2 days markedly accelerated its inhibitory effect in vitro on steroid 11β-hydroxylation in the adrenal. In contrast, irradiation of DMBA greatly reduced its activity in inhibiting 11β-hydroxylation in the adrenal. DMBA as well as its oxidative metabolite, 7-hydroxymethyl-12-methylbenz(a)anthracene (7-OHM-12-MBA), are potent inhibitors of steroid 11β-hydroxylation in the adrenal. The significance of these findings is discussed in relation to the mechanisms for protection of the adrenal cortex against injury by DMBA.