REGULATION OF HEPATIC CYTOCHROME-P450 2C11 BY GLUCOCORTICOIDS

Previous studies have shown that the expression of cytochrome P450 2C1 1 is increased in primary hepatocyte culture in the presence of 10(-8) M dexamethasone (DEX). We and others have demonstrated that injection of rats with DEX resulted in 2C11 repression, In the present study, w e show that regulation of 2C11 expression in hepatocytes by glucocorti coids is biphasic, Low concentrations (<10(-8) M) of DEX activate 2C11 expression, while higher concentrations of (>10(-7) M) suppress it, C orticosterone has a similar biphasic effect, although this physiologic al glucocorticoid was less potent than DEX, The transition between act ivation and suppression of 2C11 expression happens at glucocorticoid c oncentrations relevant to the transition between normal and stress lev els of the hormones. Both the inductive and suppressive effects of glu cocorticoids are blocked by RU486, a glucocorticoid receptor antagonis t, We postulate that the biphasic nature of the 2C11 response to gluco corticoids may result in a high sensitivity of this P450 to stressful stimuli. (C) 1997 Academic Press.