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Sensitivity of Liver Injury in Heterozygous Sod2 Knockout Mice Treated with Troglitazone or Acetaminophen
1 Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Shizuoka, Japan Correspondence: Kazunori Fujimoto, Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 717 Horikoshi, Fukuroi, Shizuoka 437-0065, Japan; e-mail:fujimoto.kazunori.wr{at}daiichisankyo.co.jp. Recently, it was reported that the intraperitoneal administration of 30 mg/kg/day troglitazone to heterozygous superoxide dismutase 2 gene knockout (Sod2+/–) mice for twenty-eight days caused liver injury, manifested by increased serum ALT activity and hepatic necrosis. Therefore, we evaluated the reproducibility of troglitazone-induced liver injury in Sod2+/– mice, as well as their validity as an animal model with higher sensitivity to mitochondrial toxicity by single-dose treatment with acetaminophen in Sod2+/– mice. Although we conducted a repeated dose toxicity study in Sod2+/– mice treated orally with 300 mg/kg/day troglitazone for twenty-eight days, no hepatocellular necrosis was observed in our study. On the other hand, six hours and twenty-four hours after an administration of 300 mg/kg acetaminophen, plasma ALT activity was significantly increased in Sod2+/– mice, compared to wild-type mice. In particular, six hours after administration, hepatic centrilobular necrosis was observed only in Sod2+/– mice. These results suggest that Sod2+/– mice are valuable as an animal model with higher sensitivity to mitochondrial toxicity. On the other hand, it was suggested that the mitochondrial damage alone might not be the major cause of the troglitazone-induced idiosyncratic liver injury observed in humans.
Key Words: Sod2+/– mice • mitochondrial toxicity • troglitazone • acetaminophen • drug-induced liver injury • hepatotoxicity Abbreviations: ALP, alkaline phosphatase • ALT, alanine aminotransferase • AST, aspartate aminotransferase • ATP, adenosine triphosphate • AUC, area under the curve • bp, base pair • Cmax, maximum drug concentration • DILI, drug-induced liver injury • DMSO, dimethyl sulfoxide • GSH, reduced glutathione • NAPQI, N-acetyl-p-benzoquinone imine • PCR, polymerase chain reaction • Sod2+/– mice, heterozygous superoxide dismutase 2 gene knockout mice • T.BIL, total bilirubin • TCA cycle, tricarboxylic acid cycle
Toxicologic Pathology, Vol. 37, No. 2,
193-200 (2009) |
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