Glucocorticoid-dependent maintenance of CYP2C11-dependent oxidation in male rat liver in vivo.
1. Hormonal factors participate in the regulation of xenobiotic metabolising enzymes in liver. Hepatic xenobiotic oxidation capacity is decreased in adrenalectomised rats, which directly implicates adrenal hormones in the control of cytochrome P450 (CYP) expression. In addition, recent studies in cultured hepatocytes have demonstrated that low concentrations of glucocorticoid upregulate the male-specific CYP2C11, which is a major enzyme that catalyses xenobiotic and steroid hydroxylations in rat liver. The present study evaluated whether glucocorticoid or mineralocorticoid may be the adrenal factor that contributes to the in vivo expression of CYP2C11 in liver. 2. Adrenalectomy of male rats selectively decreased CYP2C11-dependent 2alpha-/16alpha-hydroxylation of testosterone and other steroid substrates to 60-70% of control, whereas activities mediated by other constitutive CYPs were unaffected. The decrease in CYP2C11 activity was due to impaired protein expression in liver after adrenalectomy. Administration of dexamethasone (DEX; 0.2 mg/kg i.p. daily for 6 days) restored CYP2C11 activity and protein, whereas the mineralocorticoid deoxycorticosterone (DOC) and adrenocorticotropic hormone (ACTH) were ineffective. 3. These findings establish that glucocorticoids have a partial role in the maintenance of CYP2C11 expression and associated microsomal oxidation in liver and provide a physiological correlate for similar observations made in vitro in hepatocyte culture.
Murray
M
M
School of Physiology and Pharmacology, University of New South Wales, Sydney, Australia.
D000315:Adrenalectomy; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002458:Cell Fractionation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D003900:Desoxycorticosterone / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D008901:Mineralocorticoids / Q000494:pharmacology / Q000502:physiology; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000378:metabolism*
D005938:Glucocorticoids; D008901:Mineralocorticoids; D003900:Desoxycorticosterone; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase