Phase I and phase II drug-metabolizing enzymes are expressed and heterogeneously distributed in the biliary epithelium

Tissue expression of drug-metabolizing enzymes influences susceptibility to drugs and carcinogens. Because the biliary epithelium, exposed to bile-bor ne chemicals, may give rise to drug-induced cholangiopathies and to cholang iocarcinomas, we determined the pattern of expression of drug-metabolizing enzymes in this epithelium. We first demonstrated by blot analyses that bil iary epithelial cells (BEC) isolated from human gallbladders display cytoch rome P450 (CYP) 1A, 2E1, and 3A, microsomal epoxide hydrolase (mEH), alpha, mu, and pi glutathione S-transferase (GST), transcripts and proteins. We a lso identified CYP-associated steroid 6 beta-hydroxylase activity in BEG. C YP and mEH expression was 5- to 20-fold lower in BEC than in autologous hep atocytes, and further differed by a higher ratio of CYP3A5/CW3A4, and by CY P1A1 predominance over CYP1A2. alpha GST was highly expressed in both hepat ocytes and BEG, while pi GST was restricted to BEG. In approximately 50% of individuals, mu GST was expressed in hepatocytes and at lower levels in BE G. By using the same antibodies as those used in immunoblots, we could show by immunohistochemistry that CYP2E1, CYP3A, mEH, alpha, mu, and pi GST imm unoreactivities are expressed and display a heterogeneous distribution in t he epithelium lining the entire biliary tract except for small intrahepatic bile ducts that were devoid of CYP3A and alpha GST immunoreactivities. In conclusion, BEC contribute to phase II, and although to a lesser extent tha n hepatocytes, to phase I biotransformation. The distribution of drug-metab olizing enzymes in BEC suggest that they are heterogeneous in their ability to generate and detoxicate reactive metabolites, which may contribute to s pecific distributions of cholangiopathies.