Previous investigations demonstrated that carbon tetrachloride (CCl4) was activated by adrenal microsomes, resulting in various functional changes and ultimately in necrosis of the zona reticularis of the gland. Experiments were done to identify the adrenal P450 isozyme(s) involved in the bioactivation of CCl4. Incubation of microsomes from the zona reticularis (ZR) of the guinea pig adrenal cortex with CCl4 plus NADPH caused initiation of lipid peroxidation, covalent binding of CCl4-derived radioactivity to protein, and degradation of cytochrome(s) P450. Preincubation of the microsomal preparations with inhibitory antibodies to P450(17 alpha) or P450C21 decreased the corresponding enzyme activities (17 alpha-hydroxylation and 21-hydroxylation), but did not affect the activation of CCl4. 1-Aminobenzotriazole (ABT), a suicide inhibitor of some P450 isozymes, decreased the enzyme activities catalysed by an adrenal 52,000 Da (52 kDa) isozyme, but had no effect on the function of P450(17 alpha) or P450C21. However, ABT completely inhibited the CCl4-induced LP and covalent binding in adrenal microsomes. The results indicate that adrenal CCl4 activation is catalysed by the 52 kDa P450 isozyme and not by the steroid hydroxylases. Localization of the 52 kDa isozyme to the ZR probably accounts for the selective necrosis of this region of the gland by CCl4.

Adrenal Cortex↗

PubMedDate not supplied

Comparative effects of cadmium, zinc, and lead in vitro on pulmonary, adrenal, and hepatic microsomal metabolism in the guinea pig.

The in vitro effects of Cd, Zn, and Pb on pulmonary, adrenal, and hepatic microsomal enzyme activities in guinea pigs were compared. Cd and Zn produced concentration-dependent (20-200 microM) decreases in benzphetamine demethylase and biphenyl hydroxylase activities in adrenal, liver, and lung. Pb had no significant effect on either enzyme in any of the tissues studied. Adrenal and pulmonary enzymes were more sensitive to the effects of Cd and Zn than were hepatic enzymes. Benzo[a]pyrene hydroxylase and ethoxycoumarin deethylase activities were decreased by Zn, Cd, and Pb in adrenal, liver, and lung microsomes. The inhibitory effect on benzo[a]pyrene and ethoxycoumarin metabolism were far greater than those on benzphetamine or biphenyl metabolism. The relative potencies of the metals as inhibitors of xenobiotic metabolism were Zn greater than Cd greater than Pb. Cd and Zn also inhibited steroid 21-hydroxylase activity in adrenal microsomes, but Pb had no effect on steroid metabolism. In addition, microsomal epoxide hydratase activity in adrenal, liver, and lung was inhibited by Cd but not by Zn or Pb. The results demonstrate that adrenal and pulmonary microsomal enzymes, like those in liver, are inhibited by various metals. Inhibition of mixed-function oxidases by metals in vitro is apparently not related to changes in cytochrome P-450 levels or substrate binding to cytochrome P-450. In addition, the actions of Cd, Zn, and Pb in each tissue are highly dependent on the substrates employed.

Adrenal Glands↗