Phenobarbital induction of drug/steroid-metabolizing enzymes and nuclear receptor CAR.
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.
Kakizaki
Satoru
S
Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Yamamoto
Yukio
Y
Ueda
Akiko
A
Moore
Rick
R
Sueyoshi
Tatsuya
T
Negishi
Masahiko
M
D000624:5-Aminolevulinate Synthetase / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D002467:Cell Nucleus / Q000201:enzymology; D000090702:Constitutive Androstane Receptor; D000072467:Cytochrome P450 Family 2; D003593:Cytoplasm / Q000201:enzymology; D006801:Humans; D008099:Liver / Q000201:enzymology; D008168:Lung / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis* / Q000737:chemistry / Q000172:deficiency; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000378:metabolism; D047488:Retinoid X Receptors; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis* / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism
D000090702:Constitutive Androstane Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; D000072467:Cytochrome P450 Family 2; D000624:5-Aminolevulinate Synthetase; D010634:Phenobarbital