Abstract
Squalestatin1 (SQ1), a potent inhibitor of squalene synthase produced a dose-dependent induction of cytochromes P450 CYP2H1 and CYP3A37 mRNAs in chicken hepatoma cells. The effect of SQ1 was completely reversed by 25-hydroxycholesterol. Bile acids elicited an induction of CYP3A37 and CYP2H1 mRNA. Bile acids also reduced the phenobarbital induction of CYP2H1 but not of CYP3A37 mRNA. The effects of SQ1 and its reversal by 25-hydroxycholesterol and the effects of bile acids were reproduced in reporter gene assays with a phenobarbital-responsive enhancer unit of CYP2H1. These data suggest that an endogenous molecule related to cholesterol homeostasis regulates induction of drug-inducible CYPs.
©2002 Elsevier Science (USA).
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bile Acids and Salts / pharmacology
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Bridged Bicyclo Compounds, Heterocyclic / antagonists & inhibitors
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
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Chickens
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Cholesterol / metabolism
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Cytochrome P-450 Enzyme System / biosynthesis
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Cytochrome P-450 Enzyme System / genetics*
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Dose-Response Relationship, Drug
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Enhancer Elements, Genetic
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Enzyme Inhibitors / pharmacology*
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Farnesyl-Diphosphate Farnesyltransferase / antagonists & inhibitors*
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Genes, Reporter
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Hydroxycholesterols / pharmacology
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Phenobarbital / pharmacology
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Steroid Hydroxylases / biosynthesis
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Steroid Hydroxylases / genetics*
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Transcriptional Activation
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Tricarboxylic Acids / antagonists & inhibitors
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Tricarboxylic Acids / pharmacology*
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Tumor Cells, Cultured
Substances
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Bile Acids and Salts
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Bridged Bicyclo Compounds, Heterocyclic
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Enzyme Inhibitors
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Hydroxycholesterols
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Tricarboxylic Acids
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squalestatin 1
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25-hydroxycholesterol
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Cytochrome P-450 Enzyme System
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Cholesterol
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Steroid Hydroxylases
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steroid hormone 6-beta-hydroxylase
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Farnesyl-Diphosphate Farnesyltransferase
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Phenobarbital