Transcriptional regulation of cytochrome p450 2B genes by nuclear receptors.
Cytochrome p450 2B genes have been used extensively as prototypical models to study phenobarbital induction of p450 enzymes. Although its basal hepatic abundance is relatively low, CYP2B is highly inducible by various chemicals. Cross regulation and shared substrate specificity of CYP2B with CYP3A and other drug metabolizing enzymes lend support to the pharmacological and toxicological significance of CYP2B induction. The constitutive androstane receptor (CAR) appears to be one of the main regulators involved in transcriptional activation of CYP2B genes, although pregnane X receptor (PXR), glucocorticoids receptor (GR), and other nuclear receptors may be required for their optimal activation. In this article, we review current advances in the mechanisms of species-specific activation of CYP2B genes by CAR, with the human CYP2B6 gene being a main focus. Several recent findings, including discovery of a human CAR specific activator 6-(4-chlorophenyl:imidazo[2,1-b]thiazole-5carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO), identification of a far-distal xenobiotic-responsive enhancer module (XREM) in the CYP2B6 gene promoter, and generation of CAR-null mice as a model of characterizing CAR target gene expression, will also be discussed. These findings should provide greater insight into the mechanisms and species-specific differences of CAR regulation of CYP2B and other target genes.
Wang
Hongbing
H
School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Negishi
Masahiko
M
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D000090702:Constitutive Androstane Receptor; D065702:Cytochrome P-450 CYP2B6; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis / Q000235:genetics; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011987:Receptors, Steroid / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D013045:Species Specificity; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic; D000099148:UGT1A1 Enzyme
D001189:Aryl Hydrocarbon Hydroxylases; D000090702:Constitutive Androstane Receptor; D065702:Cytochrome P-450 CYP2B6; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D010089:Oxidoreductases, N-Demethylating; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D000099148:UGT1A1 Enzyme; C585599:CYP2B6 protein, human