title: Aryl hydrocarbon receptor ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin enhances liver damage in bile duct-ligated mice.
abstract: The environmental pollutant 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD) is known to cause a wide variety of toxic effects, including hepatotoxicity, by way of the aryl hydrocarbon receptor (AHR). Although inducible expression of cytochrome P450 (CYP) 1A1 and CYP1A2 is associated with liver injury caused by high-dose TCDD, the specific role of the AHR-CYP1 cascade in hepatotoxicity remains unclear. We investigated the effects of AHR activation under conditions of cholestasis. We administered oral TCDD to mice at a dose that can effectively induce Cyp1 gene expression without overt liver toxicity and then ligated their bile ducts. TCDD pretreatment enhanced bile duct ligation (BDL)-induced increases in liver and plasma bile acids, bilirubin, and aminotransferases. Histology of TCDD-pretreated BDL mice revealed massive hepatic necrosis without any increase in number of apoptotic cells. Whereas induction of AHR-target genes by TCDD was observed similarly in sham-operated as well as in BDL mice, TCDD pretreatment of BDL mice altered the expression of hepatic genes involved in bile acid synthesis and transport. Increased plasma proinflammatory cytokines, tumor necrosis factor and interleukin-1β, in BDL mice were further elevated by TCDD pretreatment. Liver injury by TCDD plus BDL, such as increased plasma bile acids, bilirubin and aminotransferases, liver necrosis, and increased tumor necrosis factor production, was exaggerated in Cyp1a1/1a2(-/-) double knockout mice. These findings indicate that TCDD aggravates cholestatic liver damage and that the presence of CYP1A1 and CYP1A2 plays a protective role in liver damage caused by TCDD and BDL.
authors.affiliation: Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Ozeki
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Uno
authors.forename: Michitaka
authors.initials: M
authors.lastname: Ogura
authors.forename: Mihwa
authors.initials: M
authors.lastname: Choi
authors.forename: Tetsuyo
authors.initials: T
authors.lastname: Maeda
authors.forename: Kenichi
authors.initials: K
authors.lastname: Sakurai
authors.forename: Sadanori
authors.initials: S
authors.lastname: Matsuo
authors.forename: Sadao
authors.initials: S
authors.lastname: Amano
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Nebert
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001652:Bile Ducts; D002779:Cholestasis / Q000473:pathology*; D019363:Cytochrome P-450 CYP1A1 / Q000502:physiology; D019388:Cytochrome P-450 CYP1A2 / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis; D022781:Hepatocytes / Q000473:pathology; D008026:Ligation; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*
chemical_list: D001647:Bile Acids and Salts; D016207:Cytokines; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2