RRC ID 44893
著者 Aritomi K, Ishitsuka Y, Tomishima Y, Shimizu D, Abe N, Shuto T, Irikura M, Kai H, Irie T.
タイトル Evaluation of three-dimensional cultured HepG2 cells in a nano culture plate system: an in vitro human model of acetaminophen hepatotoxicity.
ジャーナル J Pharmacol Sci
Abstract 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.
巻・号 124(2)
ページ 218-29
公開日 2014-1-1
DOI 10.1254/jphs.13135fp
PII DN/JST.JSTAGE/jphs/13135FP
PMID 24492462
MeSH Acetaminophen / antagonists & inhibitors Acetaminophen / toxicity* Acetylcysteine / pharmacology Anthracenes / pharmacology Cells, Cultured Cyclosporine / pharmacology Cytochrome P-450 CYP2E1 / metabolism Cytochrome P-450 CYP2E1 / physiology Drug Evaluation, Preclinical Glutathione / metabolism Hep G2 Cells Humans Liver / drug effects* Liver / metabolism MAP Kinase Kinase 4 / metabolism Membrane Potential, Mitochondrial / drug effects Nanotechnology / methods* Toxicity Tests / methods*
IF 2.835
引用数 13
WOS 分野 PHARMACOLOGY & PHARMACY
リソース情報
ヒト・動物細胞 Hep G2