Xenosensor Regulation of Enzymes and Transporters in Drug Exposure and Disease

Abstract

A large and varied array of xenobiotics (foreign chemicals) enters into our bodies every day. In order to prevent toxicity resulting from xenobiotic accumulation, the body has developed a complex and integrated network of enzymes and transporters to promote and control the metabolism and excretion of drugs and other compounds. Drug metabolizing enzymes are classified as oxidative (Phase I) or conjugative (Phase II), and generally result in increased hydrophilicity of their substrates. Drug transporters actively route xenobiotics into (Phase 0) or out of (Phase III) the cells. The expression of the proteins involved in drug metabolism and transport are coordinately regulated by xenosensing transcription factors, including the constitutive androstane receptor, the pregnane X receptor, the aryl hydrocarbon receptor, and Nrf2. Through the activation of these xenosensors, chemical exposure itself induces the processes which help to remove the xenobiotics from the body. The liver is the major organ of drug metabolism in the body. Chronic hepatic diseases impact the activity of xenosensors and the expression of their enzyme and transporter gene targets. Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease in the United States, affecting 20-30% of the populations. This profoundly underdiagnosed disease has significant effects on hepatic gene expression and may increase the risk of adverse drug reactions and xenobiotic toxicity in affected patients. This manuscript presents original research which contributes to our understanding of xenosensor function in the contexts of chemical exposure and liver disease. Manuscripts in this dissertation investigate 1) the induction profile and mechanisms of the experimental therapeutic agent oltipraz, 2) the xenosensor-regulated mechanisms of induction of the drug transporter ABCC3, 3) the impact of NAFLD on the expression of major drug metabolizing enzymes, and 4) the utility of altered drug disposition as a biomarker for NAFLD progression. The findings of these studies highlight the clinical importance of xenosensor activation and the potential pharmacological and toxicological consequences of hepatic disease.