Coordinate Regulation of Drug Metabolism by Xenobiotic Nuclear Receptors: UGTs Acting Together with CYPs and Glucuronide Transporters

Abstract

Xenobiotic nuclear receptors (PXR, CAR, and the Ah receptor) coordinately induce genes involved in all phases of xenobiotic metabolism including oxidative metabolism, conjugation, and transport. The comment—dedicated to honor the memory of Herbert Remmer, mentor of the author K. W. B.—discusses mechanistic, functional, and evolutionary aspects of xenobiotic nuclear receptors which induce UGTs together with CYPs and glucuronide transporters in human and rodent liver and intestine. Recent findings on regulation of CYPs, UGTs, and transporters suggest that while nuclear receptor signaling induces different CYPs, regulation may converge on single UGTs and transporters. Functional consequences of co‐regulation are discussed using examples from the metabolism of xeno‐ and endobiotics (drugs, bilirubin, bile salts, steroid hormones, and carcinogens). Animal–plant interactions may have been a major driving force in the evolutionary divergence of CYPs and UGTs in mammals and insects as well as in their regulation by nuclear receptors. In addition, regulation by nuclear receptors was probably shaped by the need for homeostatic control of endobiotic signals in the evolution of multicellular organisms.