Molecular mechanisms of cytochrome P-450 induction by xenobiotics: An expanded role for nuclear hormone receptors.

Drug exposures can lead to an increased expression of specific cytochrome P-450 proteins (P-450s) as well as of phase II drug-metabolizing enzymes that can greatly augment the metabolism and clearance of therapeutic drugs. Animal models have been used to estimate the potential of drugs to induce P-450s in humans, but differences in drug response among species hinder reliable extrapolation of observations in animals to humans. The past 2 years have witnessed a tremendous growth in our understanding of the mechanisms regulating the induction of drug metabolizing enzymes. These findings shed light on the basis for species differences in these inductive responses and will aid greatly in the development of in vitro methods to identify potential inducers of human drug-metabolizing enzymes. Drug–drug interactions are especially apparent for P-450 3A enzymes. P-450 3A4 catalyzes the metabolism of numerous commonly used drugs and is the most abundantly expressed P-450 in human liver and small intestine (Guengerich, 1999). Primary cultures of human-derived cells and established cell lines have been instrumental in the identification of potential inducers of human P-450 enzymes. These studies indicate that a variety of structurally diverse compounds induce the expression of P-450 3A4. These include the synthetic glucocorticoid dexamethasone (DEX), the macrolide antibiotic rifampicin (RIF), clotrimazole, erythromycin, lovastatine, omeprazole, and phenobarbital (PB) (Maurel, 1996). Divergent P-450 3A induction profiles are evident, however, for other species. For example, pregnenolone 16a-carbonitrile (PCN) induces rat P-450 3A23, but rabbit and human enzymes are not increased by PCN treatment. Rabbit and human P-450 3A orthologs are induced by RIF, but this compound is not an efficacious inducer of the rat P-450 enzyme (Wrighton et al., 1985; Kocarek et al., 1995). In the absence of specific information regarding the underlying molecular mechanisms mediating P-450 3A induction, the diversity of inducers and species differences suggested the potential for multiple regulatory pathways that might not be maintained in in vitro systems. Recent breakthroughs have greatly extended our understanding of the underlying mechanisms regulating P-450 expression and should facilitate the identification of inducers of human drug-metabolizing enzymes. These studies indicate that two members of the nuclear hormone receptor (NHR) family of transcription factors, the pregnane x receptor (PXR) and the constitutively active receptor (CAR), mediate the induction of P-450s 3A and 2B by xenobiotics. NHR signal transduction pathways were considered attractive mechanisms for the mediation of P-450 induction by xenobiotics, because these receptors are activated by lipophilic ligands with molecular properties similar to those of P-450 inducers. This potential was first realized with the observation that xenobiotics activate an orphan NHR, designated the peroxisome proliferator activated receptor a (PPARa) (Issemann and Green, 1990), and the demonstration that PPARa mediates the induction of P-450 4A enzymes by xenobiotics (Muerhoff et al., 1992). The basic aspects of PPARa action mirror common NHR mechanisms shared with other receptors that mediate P-450 induction. PXR, CAR, and This work was supported by United States Public Health Service Grant HD04445.