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

• Published in: BBA - General Subjects Vol. 1619; no. 3; pp. 239 - 242
• Main Authors: Kakizaki, Satoru, Yamamoto, Yukio, Ueda, Akiko, Moore, Rick, Sueyoshi, Tatsuya, Negishi, Masahiko
• Format: Book Review Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 17.02.2003
• Subjects: 5-Aminolevulinate Synthetase - biosynthesis; 5-Aminolevulinate Synthetase - genetics; Animals; Aryl Hydrocarbon Hydroxylases - biosynthesis; Aryl Hydrocarbon Hydroxylases - genetics; Cell Nucleus - enzymology; Cytochrome P450 Family 2; Cytoplasm - enzymology; Humans; Liver - enzymology; Lung - enzymology; Metabolizing enzyme; Nuclear receptor; Phenobarbital; Phenobarbital - pharmacology; 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; RNA, Messenger - biosynthesis; Steroid Hydroxylases - biosynthesis; Steroid Hydroxylases - genetics; Transcription Factors - biosynthesis; Transcription Factors - chemistry; Transcription Factors - deficiency; Transcription Factors - metabolism; Metabolizing enzyme; Nuclear receptor; Phenobarbital
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/S0304-4165(02)00482-8

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.