Effects of carbon tetrachloride on adrenocortical structure and function in guinea pigs

Abstract

Studies were carried out to evaluate the effects of carbon tetrachloride (CCl 4) on adrenocortical structure and function in guinea pigs. Treatment with CCl 4 reduced adrenal microsomal cytochrome P-450 concentrations and markedly decreased adrenal benzo(a)pyrene (BP) hydroxylase and benzphetamine (BZ) demethylase activities. Adrenal microsomal 17α- and 21-hydroxylase activities were relatively unaffected by CCl 4. Similar changes in adrenal metabolism resulted from incubation of microsomal suspension with CCl 4 plus NADPH in vitro. Morphologically, CCl 4 treatment resulted in necrotic changes in the inner portions of the adrenal cortex. The zona reticularis and inner fasciculata contained numerous cells with pyknotic nuclei, fragmented nuclei, and vacuolated cytoplasm. Cells in the outer fasciculata and zona glomerulosa of the adrenals appeared normal. In adrenals obtained from normal guinea pigs, xenobiotic metabolism was highly localized to the inner portion of the cortex, the site of CCl 4-induced necrosis. The CCl 4-induced type I spectral change, a tentative measure of binding to cytochrome(s) P-450, was also greater in microsomes from the inner than from the outer zones. In addition, the initiation of lipid peroxidation by CCl 4 plus NADPH, as well as the formation of covalently bound metabolites from 14CCl 4, was far greater with inner than outer zone microsomes. The results indicate that the effects of CCl 4 on the adrenal cortex are localized to the inner zone which probably represents the site of activation of the toxin. In addition, adrenal xenobiotic-metabolizing monooxygenases seem to be more vulnerble to the toxic effects of CCl 4 than the microsomal steroid hydroxylases.