title: Relationship between coumarin-induced hepatocellular toxicity and mitochondrial function in rats.
abstract: The manifestation of coumarin-induced hepatocellular toxicity may differ and depends on the frequency of administration to rats. A single coumarin dose induces hepatocellular necrosis while repeated doses induce only hepatocyte degeneration. However, the mechanism underlying these effects remains unclear. Therefore, we investigated the mechanism of coumarin-induced hepatotoxicity in rats. Coumarin was administered to male rats as a single dose or for 4 consecutive days, and samples were obtained 4 or 24 h after a single dose or 24 h after the repeated doses. A single coumarin dose significantly induced hepatocellular necrosis in rats; however, toxicity was attenuated after repeated dosing. With a single dose, hepatocellular necrosis was preceded by increased mitochondrial number and size and decreased mitochondrial function. An increased expression of granular cytochrome P450 (CYP) 2E1 protein was observed in the cytoplasm and mitochondria of coumarin-treated rats compared to the expression in the untreated controls. Nevertheless, repeated dosing showed mitochondrial function that was equivalent to that of the control while enlarged CYP2E1 protein droplets were distributed outside the mitochondria. These results suggest that mitochondrial function and CYP2E1 expression might be involved in coumarin-induced hepatocellular toxicity in rats. A reduction in mitochondrial CYP2E1 might be implicated in the acquisition of coumarin resistance after repeated doses.
authors.affiliation: Suntory Business Expert Limited, 8-1-1 Seikadai Seika-cho, Soraku-gun, Kyoto 619-0238, Japan; Laboratory of Pathology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge, Hirakata, Osaka 573-0101, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Suntory Business Expert Limited, 8-1-1 Seikadai Seika-cho, Soraku-gun, Kyoto 619-0238, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Fujii
authors.affiliation: Suntory Business Expert Limited, 8-1-1 Seikadai Seika-cho, Soraku-gun, Kyoto 619-0238, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Hori
authors.affiliation: Suntory Business Expert Limited, 8-1-1 Seikadai Seika-cho, Soraku-gun, Kyoto 619-0238, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kitagawa
authors.affiliation: Laboratory of Pathology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge, Hirakata, Osaka 573-0101, Japan. Electronic address: ozaki@pharm.setsunan.ac.jp.
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Ozaki
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D003374:Coumarins / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005978:Glutathione / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects*; D009336:Necrosis / Q000139:chemically induced* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D003374:Coumarins; C030123:coumarin; D000154:Aconitate Hydratase; D005978:Glutathione
keywords: CYP2E1; Coumarin; Hepatotoxicity; Mitochondria; Rat; Subcellular localization