Glucocorticoid–dependent maintenance of CYP2C11–dependent oxidation in male rat liver in vivo

Abstract

1 Hormonal factors participate in the regulation of xenobiotic metabolising enzymes in liver. Hepatic xenobiotic oxidation capacity is decreased in adrena-lectomised 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 concentra-tions 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 2a-/16a-hydroxylation of testos-terone and other steroid substrates to 60-70% of control, whereas activities mediated by other constitu-tive CYPs were unaffected. The decrease in CYP2C11 activity was due to impaired protein expression in liver after adrenalectomy. Administration of dexametha-sone (DEX; 0.2 mg/kg i.p. daily for 6 days) restored CYP2C11 activity and protein, whereas the mineralo-corticoid deoxycorticosterone (DOC) and adrenocorti-cotropic 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 observa-tions made in vitro in hepatocyte culture.

Keywords

cytochrome P450 glucocorticoid steroid hydroxyla–tion regulatio

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