title: Cytochrome P450 2E1 is responsible for the initiation of 1,2-dichloropropane-induced liver damage.
abstract: 1,2-Dichloropropane (1,2-DCP), a solvent, which is the main component of the cleaner used in the offset printing companies in Japan, is suspected to be the causative agent of bile duct cancer, which has been recently reported at high incidence in those offset printing workplaces. While there are some reports about the acute toxicity of 1,2-DCP, no information about its metabolism related to toxicity in animals is available. As part of our efforts toward clarifying the role of 1,2-DCP in the development of cancer, we studied the metabolic pathways and the hepatotoxic effect of 1,2-DCP in mice with or without cytochrome P450 2E1 (CYP2E1) activity. In an in vitro reaction system containing liver homogenate, 1,2-DCP was only metabolized by liver tissue of wild-type mice but not by that of cyp2e1-null mice. Furthermore, the kinetics of the solvent in mice revealed a great difference between the two genotypes; 1,2-DCP administration resulted in dose-dependent hepatic damage, as shown biochemically and pathologically, but this effect was only observed in wild-type mice. The nuclear factor κB p52 pathway was involved in the liver response to 1,2-DCP. Our results clearly indicate that the oxidative metabolism of 1,2-DCP in mice is exclusively catalyzed by CYP2E1, and this step is indispensable for the manifestation of the hepatotoxic effect of the solvent.
authors: Division of Health Effects Research, National Institute of Occupational Safety and Health, Kawasaki, Japan.
authors: Yukie
authors: Y
authors: Yanagiba
authors: Division of Health Effects Research, National Institute of Occupational Safety and Health, Kawasaki, Japan.
authors: Tetsuya
authors: T
authors: Suzuki
authors: Division of Health Effects Research, National Institute of Occupational Safety and Health, Kawasaki, Japan.
authors: Megumi
authors: M
authors: Suda
authors: Division of Health Effects Research, National Institute of Occupational Safety and Health, Kawasaki, Japan.
authors: Rieko
authors: R
authors: Hojo
authors: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Frank J
authors: FJ
authors: Gonzalez
authors: College of Life and Health Sciences, Chubu University, Kasugai, Japan.
authors: Tamie
authors: T
authors: Nakajima
authors: Division of Health Effects Research, National Institute of Occupational Safety and Health, Kawasaki, Japan wang@h.jniosh.go.jp.
authors: Rui-Sheng
authors: RS
authors: Wang
mesh_terms: D065767:Activation, Metabolic; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D021461:Animals, Outbred Strains; D002274:Carcinogens, Environmental / Q000008:administration & dosage / Q000032:analysis / Q000378:metabolism* / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D007306:Insecticides / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D052003:NF-kappa B p52 Subunit / Q000378:metabolism; D010084:Oxidation-Reduction; D011407:Propane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000633:toxicity; D012997:Solvents / Q000008:administration & dosage / Q000032:analysis / Q000378:metabolism* / Q000633:toxicity; D066007:Toxicokinetics
chemical_list: D002274:Carcinogens, Environmental; D007306:Insecticides; D052003:NF-kappa B p52 Subunit; C498207:Nfkb2 protein, mouse; D012997:Solvents; D019392:Cytochrome P-450 CYP2E1; C004765:propylene dichloride; D011407:Propane
keywords: 1,2-Dichloropropane; CYP2E1; DNA damage; hepatotoxicity; metabolism