title: Preliminary characterization of a murine model for 1-bromopropane neurotoxicity: Role of cytochrome P450.
abstract: Neurotoxicity of 1-bromopropane (1-BP) has been reported in both human cases and animal studies. To date, neurotoxicity of 1-BP has been induced in rats but not in mice due to the lethal hepatotoxicity of 1-BP. Oxidization by cytochromes P450 and conjugation with glutathione (GSH) are two critical metabolism pathways of 1-BP and play important roles in toxicity of 1-BP. The aim of the present study was to establish a murine model of 1-BP neurotoxicity, by reducing the hepatotoxicity of 1-BP with 1-aminobenzotriazole (1-ABT); a commonly used nonspecific P450s inhibitor. The results showed that subcutaneous or intraperitoneal injection of 1-ABT at 50mg/kg body weight BID (100mg/kg BW/day) for 3days, inhibited about 92-96% of hepatic microsomal CYP2E1 activity, but only inhibited about 62-64% of CYP2E1 activity in brain microsomes. Mice treated with 1-ABT survived even after exposure to 1200ppm 1-BP for 4 weeks and histopathological studies showed that treatment with 1-ABT protected mice from 1-BP-induced hepatic necrosis, hepatocyte degeneration, and hemorrhage. After 4-week exposure to 1-BP, the brain weight of 1-ABT(+)/1200ppm 1-BP group was decreased significantly. In 1-ABT-treated groups, expression of hippocampal Ran protein and cerebral cortical GRP78 was dose-dependently increased by exposure to 1-BP. We conclude that the control of hepatic P450 activity allows the observation of effects of 1-BP on the murine brain at a higher concentration by reduction of hepatotoxicity. The study suggests that further experiments with liver-specific control of P450 activity using gene technology might provide better murine models for 1-bromopropane-induced neurotoxicity.
authors.affiliation: Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Department of Occupational and Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510, Japan.
authors.forename: Cai
authors.initials: C
authors.lastname: Zong
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, NM 87108, USA.
authors.forename: C Edwin
authors.initials: CE
authors.lastname: Garner
authors.affiliation: Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Chinyen
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Department of Occupational and Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510, Japan.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Occupational and Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510, Japan.
authors.forename: Lingyi
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; School of Public Health, Medical College of Soochow University, Suzhou 215123, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Toyokuni
authors.affiliation: Institute for Developmental Research, Aichi Human Service Center, Kasugai 480-0392, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Occupational and Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Sakurai
authors.affiliation: Graduate School of Regional Innovation Studies, Mie University, Tsu 514-8507, Japan.
authors.forename: Sahoko
authors.initials: S
authors.lastname: Ichihara
authors.affiliation: Department of Occupational and Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510, Japan. Electronic address: gak@rs.tus.ac.jp.
authors.forename: Gaku
authors.initials: G
authors.lastname: Ichihara
mesh_terms: D000818:Animals; D001273:Atmosphere Exposure Chambers; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism / Q000401:mortality / Q000517:prevention & control; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000819:agonists / Q000378:metabolism; D006842:Hydrocarbons, Brominated / Q000008:administration & dosage / Q000633:toxicity; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D012997:Solvents / Q000008:administration & dosage / Q000633:toxicity*; D014230:Triazoles / Q000008:administration & dosage / Q000627:therapeutic use; D020931:ran GTP-Binding Protein / Q000819:agonists / Q000378:metabolism
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D006842:Hydrocarbons, Brominated; D009419:Nerve Tissue Proteins; C102460:Ran protein, mouse; D012997:Solvents; D014230:Triazoles; C033020:1-aminobenzotriazole; D003577:Cytochrome P-450 Enzyme System; D020931:ran GTP-Binding Protein; C118559:1-bromopropane
keywords: 1-Aminobenzotriazole; 1-Bromopropane; Hepatotoxicity; Murine model; Neurotoxicity; P450