title: Retinoids modulate thioacetamide-induced acute hepatotoxicity.
abstract: The literature indicates that retinoids can influence the metabolism and actions of xenobiotics and conversely that xenobiotics can influence the metabolism and actions of retinoids. We were interested in understanding the degree to which hepatic retinoid stores, accumulated over a lifetime, affect xenobiotic metabolism, and actions. To investigate this, we induced liver injury through administration of the hepatotoxin thioacetamide (TAA) to chow fed wild type (WT) mice and lecithin:retinol acyltransferase-deficient (Lrat(-/-)) mice that are genetically unable to accumulate hepatic retinoid stores. Within 48 h of TAA-treatment, WT mice develop liver injury as evidenced by focal necrotic areas and increases in serum ALT activity and myeloperoxidase activity in hepatic parenchyma. Simultaneously, features of hepatic encephalopathy develop, as evidenced by a 25% increase in blood ammonia and a threefold reduction of blood glucose levels. This is accompanied by reduced hepatic glutathione, and increased thiobarbituric acid reactive substances, protein carbonyl and sulfhydryl groups, and increased cytochrome P450-catalyzed hydroxylation activity and flavin-containing monooxygenase activity in microsomes prepared from WT liver. Strikingly, none of these TAA-induced effects were observed for matched Lrat(-/-) mice. To confirm that TAA hepatotoxicity depends on retinoid availability, we administered, over 48 h, four oral doses of 3000 IU retinyl acetate each to the mice. This led to the development of hepatotoxicity in Lrat(-/-) mice that was similar in extent to that observed in WT mice. Our findings establish that endogenous hepatic retinoid stores can modulate the toxicity of TAA in mice.
authors.affiliation: Department of Biochemistry and Biotechnology, Chernivtsi National University, Chernivtsi 58000, Ukraine.
authors.forename: Igor O
authors.initials: IO
authors.lastname: Shmarakov
authors.forename: Vira L
authors.initials: VL
authors.lastname: Borschovetska
authors.forename: Mykhailo M
authors.initials: MM
authors.lastname: Marchenko
authors.forename: William S
authors.initials: WS
authors.lastname: Blaner
mesh_terms: D000217:Acyltransferases / Q000235:genetics; D000284:Administration, Oral; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D004224:Diterpenes; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D012176:Retinoids / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use*; D000084562:Retinyl Esters; D013853:Thioacetamide / Q000633:toxicity*; D014801:Vitamin A / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D004224:Diterpenes; D012176:Retinoids; D000084562:Retinyl Esters; D013853:Thioacetamide; D014801:Vitamin A; C009166:retinol acetate; D006899:Mixed Function Oxygenases; D000217:Acyltransferases; C056942:lecithin-retinol acyltransferase
keywords: gavage; hepatic stellate cell; retinoic acid; retinyl ester; vitamin A