Phenobarbital induction of drug/steroid-metabolizing enzymes and nuclear receptor CAR

Satoru Kakizaki; Yukio Yamamoto; Akiko Ueda; Rick Moore; Tatsuya Sueyoshi; Masahiko Negishi

doi:10.1016/s0304-4165(02)00482-8

Phenobarbital induction of drug/steroid-metabolizing enzymes and nuclear receptor CAR

Biochim Biophys Acta. 2003 Feb 17;1619(3):239-42. doi: 10.1016/s0304-4165(02)00482-8.

Authors

Satoru Kakizaki¹, Yukio Yamamoto, Akiko Ueda, Rick Moore, Tatsuya Sueyoshi, Masahiko Negishi

Affiliation

¹ Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.

PMID: 12573483
DOI: 10.1016/s0304-4165(02)00482-8

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.

Publication types

Review

MeSH terms

5-Aminolevulinate Synthetase / biosynthesis
5-Aminolevulinate Synthetase / genetics
Animals
Aryl Hydrocarbon Hydroxylases / biosynthesis
Aryl Hydrocarbon Hydroxylases / genetics
Cell Nucleus / enzymology
Constitutive Androstane Receptor
Cytochrome P450 Family 2
Cytoplasm / enzymology
Humans
Liver / enzymology
Lung / enzymology
Phenobarbital / pharmacology*
RNA, Messenger / biosynthesis
Receptors, Cytoplasmic and Nuclear / biosynthesis*
Receptors, Cytoplasmic and Nuclear / chemistry
Receptors, Cytoplasmic and Nuclear / deficiency
Receptors, Retinoic Acid / chemistry
Receptors, Retinoic Acid / metabolism
Retinoid X Receptors
Steroid Hydroxylases / biosynthesis
Steroid Hydroxylases / genetics
Transcription Factors / biosynthesis*
Transcription Factors / chemistry
Transcription Factors / deficiency
Transcription Factors / metabolism

Substances

Constitutive Androstane Receptor
RNA, Messenger
Receptors, Cytoplasmic and Nuclear
Receptors, Retinoic Acid
Retinoid X Receptors
Transcription Factors
Steroid Hydroxylases
Aryl Hydrocarbon Hydroxylases
Cyp2b10 protein, mouse
Cytochrome P450 Family 2
5-Aminolevulinate Synthetase
Phenobarbital