Taosheng Chen
St. Jude Children’s Research Hospital, USA
Title: Targeting Xenobiotic Receptors PXR and CAR In Drug Toxicity and Resistance
Biography
Biography: Taosheng Chen
Abstract
Xenobiotic receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) regulate drug toxicity and resistance, which are the leading causes of treatment failure and for which no clinically safe and effective remedy is available. PXR and CAR play central roles in activating the expression of CYP3A4, a major enzyme responsible for metabolizing more than 50% of clinically prescribed drugs, and ALAS1, a rate-limiting porphyrin biosynthesis enzyme that increases the levels of hepatotoxic protoporphyrin IX (PPIX), both contributing to drug-induced liver toxicity. Elevated MDR1 level is associated with drug resistance. MDR1 expression is induced by CAR and PXR. While PXR is ligand-inducible, CAR is constitutively active. Therefore, inhibitors of PXR and CAR (i.e., antagonists of PXR and inverse agonists of CAR) may prevent drug-induced liver toxicity and overcome drug resistance. By using a chemical biology approach we have identified and optimized PXR antagonists and CAR inverse agonists, investigated their mechanisms of action by performing structural and functional analysis, and evaluated their in vivo activities by using humanized animal models. Our data indicate that it is feasible to prevent drug-induced liver toxicity and overcome drug resistance by targeting PXR and CAR using mechanism-guided chemical agents.