Regulation of Drug-metabolizing Human Cytochrome P450s

Drug-metabolizing enzymes, primarily cytochrome P450 (P450) enzymes, play central role in biotransformation, detoxication and elimination of various, structurally diverse xenobiotics. The expression of P450s is controlled by specific receptors capable of sensing xenobiotics, including notably aryl hydrocarbon receptor, a member of the Per/Arnt/Sim family of transcription factors, pregnane X receptor, constitutive androstane receptor, and peroxisome proliferators activated receptor, members of the nuclear receptor superfamily, as well as classical steroid receptors such as glucocorticoid receptor and vitamin D receptor. Because these receptors can interact with and be activated by xenobiotics, they are often designated as xenosensors. The xenobiotic signaling pathways appear to be embedded within a tangle of regulatory networks and the expression of P450s is regulated not only by xenobiotics, but also by numerous endogenous compounds (corticoids, hormones, cytokines, bile salts) frequently increased in pathophysiological conditions. Conversely, xenobiotics appear to affect the expression of genes controlling endogenous signaling pathways. The ability of nuclear receptors to control the transcription of several distinct genes suggests the existence of a complex regulatory network of metabolism of xenobiotics and endogenous compounds. This sophisticated network providing adaptive responses to many exogenous stimuli, e.g. drug treatment or exposure to chemical pollutants is discussed in this review.