title: Contributions of caspase-8 and -9 to liver injury from CYP2E1-produced metabolites of halogenated hydrocarbons.
abstract: 1. Drug-induced liver injury is difficult to predict at the pre-clinical stage. This study aimed to clarify the roles of caspase-8 and -9 in CYP2E1 metabolite-induced liver injury in both rats and cell cultures in vitro treated with carbon tetrachloride (CCl4), halothane or sevoflurane. The human hepatocarcinoma functional liver cell line was maintained in 3-dimensional culture alone or in co-culture with human acute monocytic leukemia cells. 2. In vivo, laboratory indices of liver dysfunction and histology were normal after administration of sevoflurane. CCl4treatment increased blood AST/ALT levels, liver caspase-3 and -9 activities and liver malondialdehyde, accompanied by centrilobular hepatocyte necrosis. Halothane increased AST/ALT levels, caspase-3 and -8 activities (but not malondialdehyde) concomitant with widespread hepatotoxicity. In vitro, CCl4treatment increased caspase-9 activity and decreased both mitochondrial membrane potential (MMP) and cell viability. In co-culture, halothane increased caspase-8 activity and decreased MMP and cellular viability. There were no toxic responses in CYP2E1 knockdown in monoculture and co-culture. 3. CYP2E1-inducing compounds play a pivotal role in halogenated hydrocarbon toxicity. 4. Changes in hepatocyte caspase-8 and -9 activities could be novel biomarkers of metabolites causing DILI, and in pre-clinical development of new pharmaceuticals can predict nascent DILI in the clinical stage.
authors.affiliation: a Cardiovascular Pharmacotherapy and Toxicology and.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Ijiri
authors.affiliation: a Cardiovascular Pharmacotherapy and Toxicology and.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kato
authors.affiliation: a Cardiovascular Pharmacotherapy and Toxicology and.
authors.forename: Maiko
authors.initials: M
authors.lastname: Sadamatsu
authors.affiliation: b Pharmacotherapy II, Osaka University of Pharmaceutical Sciences , Nasahara , Takatsuki , Osaka , Japan.
authors.forename: Mina
authors.initials: M
authors.lastname: Takano
authors.affiliation: a Cardiovascular Pharmacotherapy and Toxicology and.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yasuda
authors.affiliation: a Cardiovascular Pharmacotherapy and Toxicology and.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Tanaka
authors.affiliation: a Cardiovascular Pharmacotherapy and Toxicology and.
authors.forename: Chiyo
authors.initials: C
authors.lastname: Oishi
authors.affiliation: a Cardiovascular Pharmacotherapy and Toxicology and.
authors.forename: Hideki
authors.initials: H
authors.lastname: Imano
authors.affiliation: c Department of Pathology , Osaka Medical College , Daigaku-machi, Takatsuki, Osaka , Japan , and.
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Okada
authors.affiliation: d Kidney Center, Shirasagi Hospital , Kumata, Higashisumiyoshi-ku, Osaka , Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: a Cardiovascular Pharmacotherapy and Toxicology and.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hayashi
mesh_terms: D000818:Animals; D053181:Caspase 8 / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism*; D002460:Cell Line; D018920:Coculture Techniques; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D015386:Hazardous Substances / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000378:metabolism / Q000633:toxicity*; D051381:Rats
chemical_list: D015386:Hazardous Substances; D006846:Hydrocarbons, Halogenated; D019392:Cytochrome P-450 CYP2E1; D053181:Caspase 8; D053453:Caspase 9
keywords: CYP2E1 knockdown; CYP2E1 metabolite-induced liver injury; Caspase-8; FLC-4; caspase-9; three-dimensional culture