Clinical Correlates in Drug-Herbal Interactions Mediated via Nuclear Receptor PXR Activation and Cytochrome P450 Induction

Abstract

Pregnane and Xenobiotic Receptor (PXR), a vital xenosensor, acts as master regulator of phase-I (cytochrome P450) and phase-II enzymes (glutathione S-transferases, sulfotransferases, and uridine 5'-diphosphate glucuronosyltransferases) as well as several drug transporters (multi-drug resistance protein, and multidrug resistance-associated protein). PXR can bind to a variety of chemically distinct endobiotics (steroids, bile acids and their derivatives, vitamins, etc.) and xenobiotics (prescription drugs, herbal medicines, endocrine disruptors, etc.). Activation of PXR by various compounds leads to trans-activation of PXR-target genes involved in detoxification system (phase-I and phase-II enzymes, and efflux proteins). Herbal medicines are readily used without prescription under the belief that anything natural is safe. These medicines contain active chemical constituents which execute distinctly different or similar pharmacological response(s). But, like prescription drugs, herbal drugs also have both therapeutic and, sometimes, adverse effects. Some of the herbal drugs induce drug metabolizing enzymes (especially CYP3A4) and drug efflux proteins via activation of PXR. Phase-I enzyme CYP3A4 is involved in the metabolism of 50-60% of clinical drugs as well as the chemical ingredients in herbal medicines. In addition to this, 25-30% of these compounds are metabolized by the CYP2B isoenzymes. The combined metabolic effects of phase-I and phase-II enzymes and drug transporters, following induction by therapeutic molecules, constitute the molecular basis for many drug-herbal interactions. For example, if one drug activates PXR, it can encourage the elimination of a co-administered drug that is also metabolized and eliminated by PXR-target gene products, thereby affecting the therapeutic efficacy of the drug in the context of combination therapy. The present review highlights some of the recent clinical correlates in drug-herbal interactions mediated primarily via PXR and cytochrome P450.