Editorial [Hot Topic: Nuclear Hormone Receptor-Mediated Regulation of Drug Metabolizing Enzymes and Transporters (Guest Editor: Wen Xie)]

We are happy to present this hot topic issue of Current Drug Metabolism, on nuclear hormone receptor-mediated regulation of drug metabolizing enzymes and transporters. It has long been appreciated that drug-induced changes in the expression and/or activity of enzymes or transporters can affect the degree of absorption or elimination of drugs, thereby altering the therapeutic or toxicological response to a drug. The molecular mechanisms by which drugs regulate enzymes and transporter expression, have been elusive up till the 1998 cloning and characterization of pregnane X receptor (PXR), pioneered in the laboratories of Ron Evans at the Salk Institute, and Steve Kliewer then at the Glaxo Wellcome. The xenobiotic receptor identity for the constitutive androstane receptor (CAR), an orphan receptor cloned in David Moore's lab in 1994, whose physiological function was then unknown, was subsequently revealed. Since 1998, combinations of molecular biology, mouse genetics, structural biology, and drug metabolism studies have led to the conclusion that PXR and CAR can function as master regulators of the xenobiotic response by regulating both Phase I and Phase II enzymes, as well as members of the drug transporter families. Nuclear receptor-mediated xenobiotic regulation is made up of a complex regulatory network. The complexity is manifested in the observations that multiple receptors are involved in the regulation; each receptor is capable of regulating multiple xenobiotic targets; there is extensive cross talk between receptors; and many xenobiotic receptors exhibit a distinctive, yet overlapping, spectrum of ligands. Finally, the receptor-mediated enzyme and transporter regulation can not only effect drug metabolism, but it can also influence many patho-physiological processes by affecting the homeostasis of endogenous chemicals such as bile acids, bilirubin, and steroid hormones. I would like to personally thank all of the contributing authors, who are experts and are in the forefront of this emerging and exciting research field. Special thanks goes to Dr. Chandra Prakash, Editor-in-Chief of Current Drug Metabolism, who proposed this hot topic issue to me, at the "2004 Gordon Conference on Drug Metabolism".