Regulation of the Human UGT1A1 Gene by Nuclear Receptors Constitutive Active/Androstane Receptor, Pregnane X Receptor, and Glucocorticoid Receptor

Human UDP‐glucuronosyltransferase (UGT) 1A1 is the enzyme that detoxifies neurotoxic bilirubin by conjugating it with glucuronic acid. In addition to bilirubin, UGT1A1 conjugates various endogenous and exogenous lipophilic compounds such as estrogens and the active metabolite of the anticancer drug irinotecan SN‐38. Thus, activation by specific inducers of the UGT1A1 gene is critical in treating patients with unconjugated hyperbili‐rubinemia and in preventing side effects of drug treatment such as SN‐38‐induced toxicity. This chapter describes the experimental processes used to identify the 290‐bp distal enhancer module at −3499/−3210 of the UGT1A1 gene and to characterize its regulation by nuclear receptors: constitutive active/androstane receptor, pregnane X receptor, and glucocorticoid receptor.