Abstract
Phenobarbital (PB) increases hepatic drug/steroid-metabolic capability by coordinately activating transcription of the genes encoding various metabolizing enzymes. The nuclear receptor CAR was first implicated as a transcription factor that activates the cytochrome P450 Cyp2b10 gene. In response to PB, CAR forms a heterodimer with the retinoid X receptor (RXR), binds to a PB response element (typified by DR-4 motif), and activates transcription of the gene. In the CAR-null mouse, PB does not only induce the Cyp2b10 gene, but also induces genes encoding various metabolizing enzymes. Thus, CAR is a general nuclear receptor that is essential for PB induction of drug/steroid metabolizing enzymes. PB also induces amino levulinate synthase 1 (ALAS-1), the rate-limiting enzyme in heme biosynthesis, to increase heme supply. However, PB induction of the synthase occurs in CAR-null mice, suggesting that CAR does not coordinate the heme synthesis for the induction of drug/steroid metabolism.
MeSH terms
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5-Aminolevulinate Synthetase / biosynthesis
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5-Aminolevulinate Synthetase / genetics
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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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Cell Nucleus / enzymology
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Constitutive Androstane Receptor
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Cytochrome P450 Family 2
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Cytoplasm / enzymology
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Humans
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Liver / enzymology
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Lung / enzymology
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Phenobarbital / pharmacology*
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RNA, Messenger / biosynthesis
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Receptors, Cytoplasmic and Nuclear / biosynthesis*
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Receptors, Cytoplasmic and Nuclear / chemistry
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Receptors, Cytoplasmic and Nuclear / deficiency
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Receptors, Retinoic Acid / chemistry
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Receptors, Retinoic Acid / metabolism
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Retinoid X Receptors
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Steroid Hydroxylases / biosynthesis
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Steroid Hydroxylases / genetics
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Transcription Factors / biosynthesis*
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Transcription Factors / chemistry
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Transcription Factors / deficiency
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Transcription Factors / metabolism
Substances
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Constitutive Androstane Receptor
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RNA, Messenger
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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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Steroid Hydroxylases
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Aryl Hydrocarbon Hydroxylases
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Cyp2b10 protein, mouse
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Cytochrome P450 Family 2
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5-Aminolevulinate Synthetase
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Phenobarbital