Abstract
CYP3A4 and CYP3A7 mRNA expression levels were markedly up-regulated by dexamethasone (DEX), but not by rifampicin (RIF). CYP3A5 mRNA level was not increased significantly by DEX, RIF, or phenobarbital. Testosterone 6beta-hydroxylase activity was induced to about 2-fold of control by DEX. However, concomitant treatment with RIF did not alter DEX-mediated induction of CYP3A mRNA expression and testosterone 6beta-hydroxylase activity. DEX-mediated induction of CYP3A mRNA was suppressed in a dose-dependent manner by RU486, a glucocorticoid receptor (GR) antagonist. At 5microM RU486, DEX-mediated induction of CYP3A4, CYP3A5, and CYP3A7 mRNA expression was inhibited almost completely. These results suggest that, in human fetal hepatocytes, PXR is not involved in DEX-mediated induction of CYP3A4 and CYP3A7, and that the induction is mediated directly by GR.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Aryl Hydrocarbon Hydroxylases / biosynthesis*
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Aryl Hydrocarbon Hydroxylases / genetics
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Blotting, Western
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Cells, Cultured
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Cytochrome P-450 CYP3A
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Cytochrome P-450 Enzyme System / biosynthesis*
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Cytochrome P-450 Enzyme System / genetics
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Dexamethasone / pharmacology
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Enzyme Induction / drug effects
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Enzyme Inhibitors / pharmacology
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Fetus
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Hepatocytes / cytology
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Hepatocytes / enzymology*
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Humans
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Insecta / cytology
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Microsomes / metabolism
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Mifepristone / pharmacology
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Phenobarbital / pharmacology
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RNA, Messenger / biosynthesis
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Receptors, Glucocorticoid / antagonists & inhibitors
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Rifampin / pharmacology
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Tretinoin / chemistry
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Tretinoin / pharmacology
Substances
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Enzyme Inhibitors
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RNA, Messenger
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Receptors, Glucocorticoid
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Mifepristone
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Tretinoin
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Dexamethasone
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Cytochrome P-450 Enzyme System
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Aryl Hydrocarbon Hydroxylases
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CYP3A protein, human
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CYP3A5 protein, human
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CYP3A7 protein, human
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human
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Rifampin
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Phenobarbital