Drug Metabolism: Evolution

Nebert, Daniel W.

doi:10.1002/9780470015902.a0006143

Cited by 1 publication

(1 citation statement)

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“…The ability to clear these chemicals from our bodies is essential to survival, so naturally, mechanisms that metabolize and excrete these xenobiotics have evolved [36]. Xenobiotics metabolism and disposition are mediated by a large number of DMEs and transporters, and consist of four major stages: absorption/permeability, distribution, metabolism, and excretion.…”

Section: Drug Biotransformation Metabolism and Excretion Systemsmentioning

confidence: 99%

Nuclear receptors in the multidrug resistance through the regulation of drug-metabolizing enzymes and drug transporters

Chen

Tang

Guo

et al. 2012

Biochemical Pharmacology

186

130

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Chemotherapy is one of the three most common treatment modalities for cancer. However, its efficacy is limited by multidrug resistant cancer cells. Drug metabolizing enzymes (DMEs) and efflux transporters promote the metabolism, elimination, and detoxification of chemotherapeutic agents. Consequently, elevated levels of DMEs and efflux transporters reduce the therapeutic effectiveness of chemotheraputics and, often, lead to treatment failure. Nuclear receptors, especially pregnane X receptor (PXR, NR1I2) and constitutive androstane activated receptor (CAR, NR1I3), are increasingly recognized for their role in xenobiotic metabolism and clearance as well as their role in the development of multidrug resistance (MDR) during chemotherapy. Promiscuous xenobiotic receptors, including PXR and CAR, govern the inducible expressions of a broad spectrum of target genes that encode phase I DMEs, phase II DMEs, and efflux transporters. Recent studies conducted by a number of groups, including ours, have revealed that PXR and CAR play pivotal roles in the development of MDR in various human carcinomas, including prostate, colon, ovarian, and esophageal squamous cell carcinomas. Accordingly, PXR/CAR expression levels and/or activation statuses may predict prognosis and identify the risk of drug resistance in patients subjected to chemotherapy. Further, PXR/CAR antagonists, when used in combination with existing chemotherapeutics that activate PXR/CAR, are feasible and promising options that could be utilized to overcome or, at least, attenuate MDR in cancer cells.

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Section: Drug Biotransformation Metabolism and Excretion Systemsmentioning

confidence: 99%