DIFFERENTIAL-EFFECTS OF ADRENOCORTICOTROPIN IN-VIVO ON CYTOCHROMES P4502D16 AND P450C17 IN THE GUINEA-PIG ADRENAL-CORTEX

Studies were performed to compare the effects of ACTH treatment in viv o on cytochromes P4502D16 and P450c17 in the guinea pig adrenal cortex . In untreated animals, CYP2D16 protein and messenger RNA (mRNA) expre ssion as well as xenobiotic-metabolizing activities (bufuralol 1'-hydr oxylase, benzphetamine N-demethylase, and benzo(a)pyrene hydroxylase) were far greater in the inner (zona reticularis) than the outer (zona fasciculata plus zona glomerulosa) zones of the cortex. ACTH treatment for 3 or 7 days significantly decreased the rates of xenobiotic metab olism in both the inner and outer adrenal zones. Western and Northern blot analyses revealed that adrenal CYP2D16 protein and mRNA concentra tions were significantly decreased by ACTH. In contrast to its inhibit ory effects on CYP2D16, ACTH treatment increased steroid 17 alpha-hydr oxylase activity in the adrenal inner zone, but did not affect outer z one activity. Microsomal CYP17 protein concentrations were not affecte d by ACTH despite increases in CYP17 mRNA levels in both zones. The re sults indicate that ACTH causes down-regulation of adrenal CYP2D16, pr obably at the transcriptional level. Thus, modulation of CYP2D16 by AC TH is opposite that for the steroidogenic P450 isozymes, suggesting un ique regulatory mechanisms. In addition, the data suggest that posttra nscriptional mechanisms contribute to ACTH regulation of 17 alpha-hydr oxylase activity in the guinea pig adrenal cortex.