Transcriptional regulation of cytochrome p450 2B genes by nuclear receptors

Abstract

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.