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Evaluation of three-dimensional cultured HepG2 cells in a nano culture plate system: An in vitro human model of acetaminophen hepatotoxicity
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نویسنده
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aritomi k. ,ishitsuka y. ,tomishima y. ,shimizu d. ,abe n. ,shuto t. ,irikura m. ,kai h. ,irie t.
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منبع
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journal of pharmacological sciences - 2014 - دوره : 124 - شماره : 2 - صفحه:218 -229
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چکیده
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Overdoses of acetaminophen (paracetamol,n-acetyl-p-aminophenol; apap) cause severe liver injury,yet there is no common or high throughput in vitro human apap model. this study examined the characteristics and usefulness of hepg2 cells grown in a nano culture plate (ncp) system,a three-dimensional culture method,as an in vitro human model for apap-induced hepatotoxicity. the ncp-cultured hepg2 cells showed higher expression of mrna and protein levels of cytochrome p450 2e1,which metabolizes apap to a toxic metabolite,apap-cysteine adduct formation,and higher sensitivity against apap-induced cell injury compared with conventionally cultured cells. we demonstrated that treatment of apap in ncp-cultured hepg2 cells shows key mechanistic features of apap-induced hepatotoxicity,such as decreases in intracellular glutathione and mitochondrial membrane potential,activation of jnk,and cellular injury; and pharmacological agents,such as cyclosporine a (a mitochondrial permeability transition inhibitor) and sp600125 (a jnk inhibitor),prevented cell injury induced by apap exposure. in addition,the antidote of apap-induced hepatotoxicity,n-acetylcysteine,could attenuate cellular injury induced by apap in ncp-cultured hepg2 cells. we suggest that cellular injury induced by apap treatment using an ncp-hepg2 system is a useful human model to study mechanisms and screen drug candidates of apap-induced hepatotoxicity. © 2014 the japanese pharmacological society.
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کلیدواژه
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Acetaminophen; HepG2 cell; Human model; Liver injury; Three-dimensional culture
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آدرس
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department of clinical chemistry and informatics,graduate school of pharmaceutical sciences,kumamoto university,5-1 oe-honmachi,chuo-ku,kumamoto 862-0973, Japan, department of clinical chemistry and informatics,graduate school of pharmaceutical sciences,kumamoto university,5-1 oe-honmachi,chuo-ku,kumamoto 862-0973, Japan, department of clinical chemistry and informatics,graduate school of pharmaceutical sciences,kumamoto university,5-1 oe-honmachi,chuo-ku,kumamoto 862-0973, Japan, department of clinical chemistry and informatics,graduate school of pharmaceutical sciences,kumamoto university,5-1 oe-honmachi,chuo-ku,kumamoto 862-0973, Japan, department of clinical chemistry and informatics,graduate school of pharmaceutical sciences,kumamoto university,5-1 oe-honmachi,chuo-ku,kumamoto 862-0973, Japan, department of molecular medicine,graduate school of pharmaceutical sciences,kumamoto university,5-1 oe-honmachi,chuo-ku,kumamoto 862-0973, Japan, department of clinical chemistry and informatics,graduate school of pharmaceutical sciences,kumamoto university,5-1 oe-honmachi,chuo-ku,kumamoto 862-0973, Japan, department of molecular medicine,graduate school of pharmaceutical sciences,kumamoto university,5-1 oe-honmachi,chuo-ku,kumamoto 862-0973, Japan, department of clinical chemistry and informatics,graduate school of pharmaceutical sciences,kumamoto university,5-1 oe-honmachi,chuo-ku,kumamoto 862-0973,japan,center for clinical pharmaceutical sciences,faculty of pharmaceutical sciences,kumamoto university,5-1 oe-honmachi,chuo-ku,kumamoto 862-0973, Japan
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Authors
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