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

Abstract

Tissue expression of drug-metabolizing enzymes influences susceptibility to drugs and carcinogens. Because the biliary epithelium, exposed to bile-borne chemicals, may give rise to drug-induced cholangiopathies and to cholangiocarcinomas, we determined the pattern of expression of drug-metabolizing enzymes in this epithelium. We first demonstrated by blot analyses that biliary epithelial cells (BEC) isolated from human gallbladders display cytochrome P450 (CYP) 1A, 2E1, and 3A, microsomal epoxide hydrolase (mEH), ␣, , and glutathione S-transferase (GST), transcripts and proteins. We also identified CYPassociated steroid 6␤-hydroxylase activity in BEC. CYP and mEH expression was 5-to 20-fold lower in BEC than in autologous hepatocytes, and further differed by a higher ratio of CYP3A5/CYP3A4, and by CYP1A1 predominance over CYP1A2. ␣GST was highly expressed in both hepatocytes and BEC, while GST was restricted to BEC. In approximately 50% of individuals, GST was expressed in hepatocytes and at lower levels in BEC. By using the same antibodies as those used in immunoblots, we could show by immunohistochemistry that CYP2E1, CYP3A, mEH, ␣, , and GST immunoreactivities are expressed and display a heterogeneous distribution in the epithelium lining the entire biliary tract except for small intrahepatic bile ducts that were devoid of CYP3A and ␣GST immunoreactivities. In conclusion, BEC contribute to phase II, and although to a lesser extent than hepatocytes, to phase I biotransformation. The distribution of drug-metabolizing enzymes in BEC suggest that they are heterogeneous in their ability to generate and detoxicate reactive metabolites, which may contribute to specific distributions of cholangiopathies. (HEPATOLOGY 1999;30:1498-1506.)Foreign compounds including procarcinogens and drugs are widely distributed in our environment. The liver is the major organ responsible for their biotransformation into more hydrophilic products, and elimination through bile secretion. Biotransformation results from the activities of phase I and phase II metabolizing enzymes that are mainly, although not exclusively, located within hepatocytes.

Slow acetylator genotype of N-acetyl transferase2 (NAT2) is associated with increased susceptibility to gallbladder cancer; The cancer risk not modulated by gallstone disease

“…The presence of drug-metabolizing enzymes in billiary epithelium cells suggests heterogeneous ability to detoxicate reactive metabolites. 15 Polymorphisms of several of these genes are believed to be key factors in determining cancer susceptibility to toxic or environmental chemicals. [14][15][16] An individual predisposition to various cancers has also been linked to the environmental factors and NAT2 genotypes.…”

Liver-Targeted Drug Delivery Using HepDirect Prodrugs

“…Liver targeting is principally attributed to the susceptibility of HepDirect prodrugs to oxidation by a liver enzyme, CYP3A, coupled with their stability in aqueous solutions, blood, and most nonhepatic tissues (Erion et al, 2004). Since CYP3A is expressed predominantly in hepatocytes and is either absent or present at very low levels in other liver cells, e.g., stellate cells (Parola et al, 1997), Kupffer cells, endothelial cells, and biliary epithelial cells (Lakehal et al, 1999), HepDirect prodrugs not only target the liver but more specifically target the hepatocyte. Other factors affecting the magnitude of liver targeting and overall extrahepatic drug exposure include the ability of the hepatocyte to retain prodrug cleavage products and the pathways involved in the subsequent elimination of these products.…”

Blood-Brain Barrier P450 Enzymes and Multidrug Transporters in Drug Resistance: A Synergistic Role in Neurological Diseases

“…For example, carbamazepine (first generation AED) is a substrate and an inducer of hepatic CYP3A4 [26,[38][39][40]44] while phenytoin serum levels are determined by CYP2C9 and CYP2C19 [38,44,45]. The metabolism of carbamazepine is decreased by the co-administration of valproic acid, leading to an increased risk of carbamazepine toxicity [26,39,40].…”