Thioacetamide-induced Hepatocellular Necrosis Is Attenuated in Diet-induced
Obese Mice |
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Authors: | Makoto Shirai Shingo Arakawa Hiroaki Miida Takuya Matsuyama Junzo Kinoshita Toshihiko Makino Kiyonori Kai Munehiro Teranishi |
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Institution: | 1. Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 717 Horikoshi, Fukuroi, Shizuoka 437-0065, Japan |
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Abstract: | To assess modification of thioacetamide-induced hepatotoxicity in mice fed a high-fat
diet, male C57BL/6J mice were fed a normal rodent diet or a high-fat diet for 8 weeks and
then treated once intraperitoneally with thioacetamide at 50 mg/kg body weight. At 24 and
48 hours after administration, massive centrilobular hepatocellular necrosis was observed
in mice fed the normal rodent diet, while the necrosis was less severe in mice fed the
high-fat diet. In contrast, severe swelling of hepatocytes was observed in mice fed the
high-fat diet. In addition, mice fed the high-fat diet displayed more than a 4-fold higher
number of BrdU-positive hepatocytes compared with mice fed the normal rodent diet at 48
hours after thioacetamide treatment. To clarify the mechanisms by which the hepatic
necrosis was attenuated, we investigated exposure to thioacetamide and one of its
metabolites, the expression of CYP2E1, which converts thioacetamide to reactive
metabolites, and the content of glutathione S-transferases in the liver. However, the
reduced hepatocellular necrosis noted in mice fed the high-fat diet could not be explained
by the differences in exposure to thioacetamide or thioacetamide sulfoxide or by
differences in the expression of drug-metabolizing enzymes. On the other hand, at 8 hours
after thioacetamide administration, hepatic total glutathione in mice fed the high-fat
diet was significantly lower than that in mice fed the normal diet. Hence, decreased
hepatic glutathione amount is a candidate for the mechanism of the attenuated necrosis. In
conclusion, this study revealed that thioacetamide-induced hepatic necrosis was attenuated
in mice fed the high-fat diet. |
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Keywords: | obese mouse high-fat diet thioacetamide nonalcoholic fatty liver disease liver |
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