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-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), alpha, mu, and pi glutathione S-transferase (GST), transcripts and proteins. We also identified CYP-associated steroid 6beta-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. alphaGST was highly expressed in both hepatocytes and BEC, while piGST was restricted to BEC. In approximately 50% of individuals, muGST 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, alpha, mu, and piGST 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 alphaGST 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.
Lakehal
F
F
Unité INSERM U402, Faculté de Médecine Saint-Antoine, Paris, France.
Wendum
D
D
Barbu
V
V
Becquemont
L
L
Poupon
R
R
Balladur
P
P
Hannoun
L
L
Ballet
F
F
Beaune
P H
PH
Housset
C
C
D001189:Aryl Hydrocarbon Hydroxylases; D001659:Biliary Tract / Q000201:enzymology*; D001711:Biotransformation; D015153:Blotting, Western; D002478:Cells, Cultured; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000201:enzymology; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism; D005704:Gallbladder / Q000166:cytology / Q000201:enzymology*; D015870:Gene Expression; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000201:enzymology; D008861:Microsomes / Q000201:enzymology; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D013250:Steroid Hydroxylases / Q000378:metabolism
D007527:Isoenzymes; D004364:Pharmaceutical Preparations; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; C022657:steroid hormone 6-beta-hydroxylase; D010089:Oxidoreductases, N-Demethylating; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases