Alteration of Acetaminophen-induced Cytotoxicity in Mouse Hepatocytes during Primary Culture
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概要
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The present study investigated issues regarding cytotoxicity tests using mouse hepatocytes in primary culture. The results indicated that the cytotoxicity of acetaminophen (APAP) markedly varied depending on culture period for up to 5 days. P450 isoforms involved in the activation of APAP, such as CYP1A2, CYP2E1, and CYP3A, showed a marked decrease in expressions of respective mRNA. Their expression levels were a few percent within 24 hr after the start of the culture, and remained low throughout. Meanwhile, the mRNA expression of enzymes involved in the detoxification of APAP, UGT1A6 and SULT1A1, declined moderately and then recovered to approximately 40% of the in vivo level later in the culture. Treatment with APAP at non-cytotoxic concentrations increased expressions of CYP1A2, CYP2E1, CYP3A11 and CYP3A41 mRNA, while it decreased that of SULT1A1 mRNA. Using the lactate dehydrogenase (LDH) assay, the cells treated with 25-mM APAP for 24-48 or 48-72 hr showed higher cytotoxicity values than those for 72-96 or 96-120 hr, but the values after 50-mM treatment were completely inverted. By employing the methylthiazolyl tetrazolium (MTT) assay, culture period-dependent cytotoxicity was also observed on 25-mM APAP treatment, but this was not clear at 50 mM. Lower LDH or higher MTT activities than the control were observed in cells treated with lower concentrations of APAP, becoming the more prominent the longer the culture period. The observations suggested that, since the expression of metabolizing enzymes alters markedly during the primary culture and the range of cytotoxic concentrations of a test compound varies depending on the culture period, it is necessary to take account of these fluctuating parameters when assessing the cytotoxic character of a compound.
- 公益社団法人 日本薬学会の論文
著者
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Kawasaki Yuki
Department of Toxicology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toy
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JARUCHOTIKAMOL Atika
Department of Toxicology, Faculty of Pharmaceutical Sciences, University of Toyama
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Sakuma Tsutomu
Department Of Bioscience And Chemistry Faculty Of Agriculture Hokkaido Unversity
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Nemoto Nobuo
Department Of Experimental Pathology Cancer Institute
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Kondo Sachiko
Department of Toxicology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toy
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Takase Akiko
Department of Toxicology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toy
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Itoh Sumiyo
Department of Toxicology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toy
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Kawasaki Yuki
Department Of Chemistry Graduate School Of Pure And Applied Sciences University Of Tsukuba
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Kondo Sachiko
Department of Applied Biological Science, Fukuyama University
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Itoh Sumiyo
Department of Toxicology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
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Takase Akiko
Department of Toxicology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
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