Abstract
The effects of 5alpha-androsten-3alpha-ol (ASE), and retinoic acids (RAs) and their precursors on the phenobarbital (PB)-mediated induction of CYP2B1 and 2B2 were examined in cultured rat hepatocytes. Two isomers of RA, 9-cis- and all-trans-RA, suppressed markedly the effect of PB on CYP2B1/2 expression, while ASE had no suppressive effect. The effect of 9-cis-RA appeared at a lower concentration than the all-trans-isomer, indicating the dominant action of the former isomer. Suppression with 9-cis-retinal was also observed, but all-trans-retinol and -retinal were without effect. These results suggest that: (1) ASE, an inverse agonist for the constitutive androstane receptor (CAR), does not play a major role in the suppression of the CYP2B; (2) 9-cis-RA suppresses CYP2B induction by reducing ligand-free retinoid X-receptors (RXR) available for dimerization with the CAR; and (3) enzymes responsible for RA formation play an important role in the mechanism governing CYP2B regulation.
Copyright 2000 Academic Press.
MeSH terms
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Androstenols / pharmacology
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Animals
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Aryl Hydrocarbon Hydroxylases*
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Cells, Cultured
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Constitutive Androstane Receptor
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Cytochrome P-450 CYP2B1 / antagonists & inhibitors
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Cytochrome P-450 CYP2B1 / genetics*
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Cytochrome P-450 CYP2B1 / metabolism
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Cytochrome P-450 Enzyme Inhibitors
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Cytochrome P-450 Enzyme System / genetics*
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Cytochrome P-450 Enzyme System / metabolism
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Dimerization
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Dose-Response Relationship, Drug
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Down-Regulation / drug effects
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Enzyme Induction / drug effects*
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Hepatocytes / enzymology
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Hepatocytes / metabolism
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Immunoblotting
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Isomerism
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Ligands
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Liver / cytology
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Liver / enzymology
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Liver / metabolism
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Male
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Phenobarbital / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Receptors, Cytoplasmic and Nuclear / metabolism
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Receptors, Retinoic Acid / metabolism
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Retinoid X Receptors
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Steroid Hydroxylases / antagonists & inhibitors
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Steroid Hydroxylases / genetics*
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Steroid Hydroxylases / metabolism
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Transcription Factors / metabolism
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Tretinoin / pharmacology*
Substances
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Androstenols
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Constitutive Androstane Receptor
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Cytochrome P-450 Enzyme Inhibitors
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Ligands
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Receptors, Cytoplasmic and Nuclear
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Receptors, Retinoic Acid
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Retinoid X Receptors
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Transcription Factors
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androst-5-en-3-ol
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Tretinoin
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Cytochrome P-450 Enzyme System
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Steroid Hydroxylases
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Aryl Hydrocarbon Hydroxylases
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Cytochrome P-450 CYP2B1
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steroid 16-beta-hydroxylase
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Phenobarbital