Regulation of hepatic cytochrome P450 2C11 by glucocorticoids.
Previous studies have shown that the expression of cytochrome P450 2C11 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, we show that regulation of 2C11 expression in hepatocytes by glucocorticoids is biphasic. Low concentrations (<10(-8) M) of DEX activate 2C11 expression, while higher concentrations of (>10(-7) M) suppress it. Corticosterone has a similar biphasic effect, although this physiological glucocorticoid was less potent than DEX. The transition between activation and suppression of 2C11 expression happens at glucocorticoid concentrations relevant to the transition between normal and stress levels of the hormones. Both the inductive and suppressive effects of glucocorticoids are blocked by RU486, a glucocorticoid receptor antagonist. We postulate that the biphasic nature of the 2C11 response to glucocorticoids may result in a high sensitivity of this P450 to stressful stimuli.
Iber
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Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Chen
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Sewer
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Morgan
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ET
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002469:Cell Separation; D002478:Cells, Cultured; D003345:Corticosterone / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic; D006727:Hormone Antagonists / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008861:Microsomes / Q000201:enzymology; D015735:Mifepristone / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000096:biosynthesis*
D006727:Hormone Antagonists; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase; D003345:Corticosterone