Hepatic bile acid metabolism and expression of cytochrome P450 and related enzymes are altered in Bsep −/− mice

摘要: The bile salt export pump (BSEP/Bsep; gene symbol ABCB11/Abcb11) translocates salts across the hepatocyte canalicular membrane into in humans and mice. In humans, mutations ABCB11 cause a severe childhood liver disease known as progressive familial intrahepatic cholestasis type 2. Targeted inactivation of mouse Bsep produces milder persistent due to detoxification acids through hydroxylation alternative transport pathways. purpose present study was determine whether functional expression hepatic cytochrome P450 (CYP) microsomal epoxide hydrolase (mEH) is altered by mice regulate CYP mEH (-/-) determined measuring protein levels Cyp2b, Cyp2c Cyp3a enzymes CYP-mediated activities including lithocholic acid hydroxylation, testosterone alkoxyresorufin O-dealkylation microsomes prepared from female male fed normal or cholic (CA)-enriched diet. results indicated that catalyzed Cyp3a/Cyp3a11 3-ketocholanoic murideoxycholic were major metabolites. CA feeding increased Cyp3a11 Cyp3a11-mediated 2β-, 6β-, 15β-hydroxylation activities, Cyp2b10 Cyp2b10-mediated benzyloxyresorufin O-debenzylation activity, elevated Cyp2c29 levels. We propose upregulate Cyp3a11, Cyp2b10, multidrug resistance-1 P-glycoproteins (Mdr1a/1b) are vital components two distinct pathways utilized hepatocytes expel acids.