Nuclear receptor-mediated regulation of cytochrome P450 genes

Abstract

Nuclear receptors such as aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), and constitutive androstane receptor (CAR) were first characterized as ligand-bound transcription factors that directly bind their response DNA sequences to regulate cytochrome P450 (CYP) genes. This simple ligand mechanism has evolved into more complex mechanisms in order for us to understand the high specificity and enormous diversity of regulation mediated at various stages by nuclear receptors, including intracellular localization, proteasome-mediated degradation, chromatin-based arrangement, epigenetic modifications, selective recruitment of co-regulators, and cross talk between nuclear receptors. Cell signaling has become a critical regulator that determines various nuclear receptor actions. These nuclear receptors, particularly in CAR, can now be considered as cell signal-regulated nuclear receptors. Through studies of their induction, the cytochrome P450s, once thought to catalyze the oxidation of xenobiotics and therapeutic drugs, are now found to regulate liver functions by metabolizing key endogenous stimuli such as cholesterol, bile acids, and steroid hormones. Recent research on nuclear receptors and CYP induction is creating excitement and is redefining their functions and mechanisms into new frontiers.