title: Intestinal CYP3A4 protects against lithocholic acid-induced hepatotoxicity in intestine-specific VDR-deficient mice.
abstract: Vitamin D receptor (VDR) mediates vitamin D signaling involved in bone metabolism, cellular growth and differentiation, cardiovascular function, and bile acid regulation. Mice with an intestine-specific disruption of VDR (Vdr(ΔIEpC)) have abnormal body size, colon structure, and imbalance of bile acid metabolism. Lithocholic acid (LCA), a secondary bile acid that activates VDR, is among the most toxic of the bile acids that when overaccumulated in the liver causes hepatotoxicity. Because cytochrome P450 3A4 (CYP3A4) is a target gene of VDR-involved bile acid metabolism, the role of CYP3A4 in VDR biology and bile acid metabolism was investigated. The CYP3A4 gene was inserted into Vdr(ΔIEpC) mice to produce the Vdr(ΔIEpC)/3A4 line. LCA was administered to control, transgenic-CYP3A4, Vdr(ΔIEpC), and Vdr(ΔIEpC)/3A4 mice, and hepatic toxicity and bile acid levels in the liver, intestine, bile, and urine were measured. VDR deficiency in the intestine of the Vdr(ΔIEpC) mice exacerbates LCA-induced hepatotoxicity manifested by increased necrosis and inflammation, due in part to over-accumulation of hepatic bile acids including taurocholic acid and taurodeoxycholic acid. Intestinal expression of CYP3A4 in the Vdr(ΔIEpC)/3A4 mouse line reduces LCA-induced hepatotoxicity through elevation of LCA metabolism and detoxification, and suppression of bile acid transporter expression in the small intestine. This study reveals that intestinal CYP3A4 protects against LCA hepatotoxicity.
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Jie
authors.initials: J
authors.lastname: Cheng
authors.forename: Zhong-Ze
authors.initials: ZZ
authors.lastname: Fang
authors.forename: Jung-Hwan
authors.initials: JH
authors.lastname: Kim
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.forename: Naoki
authors.initials: N
authors.lastname: Tanaka
authors.forename: John Y L
authors.initials: JY
authors.lastname: Chiang
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism* / Q000652:urine; D005704:Gallbladder / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D008095:Lithocholic Acid; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D055432:Metabolomics / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018167:Receptors, Calcitriol / Q000172:deficiency* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001647:Bile Acids and Salts; D018167:Receptors, Calcitriol; D008095:Lithocholic Acid; D002784:Cholesterol; D051544:Cytochrome P-450 CYP3A; C000592551:cytochrome P450 3A4, mouse
keywords: bile acids; metabolomics; vitamin D receptor