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Cytochrome P450 2E1 is responsible for the initiation of 1,2-dichloropropane-induced liver damage.
- Source :
-
Toxicology and industrial health [Toxicol Ind Health] 2016 Sep; Vol. 32 (9), pp. 1589-97. Date of Electronic Publication: 2015 Feb 13. - Publication Year :
- 2016
-
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.<br /> (© The Author(s) 2015.)
- Subjects :
- Activation, Metabolic
Active Transport, Cell Nucleus drug effects
Animals
Animals, Outbred Strains
Carcinogens, Environmental administration & dosage
Carcinogens, Environmental analysis
Carcinogens, Environmental toxicity
Chemical and Drug Induced Liver Injury blood
Chemical and Drug Induced Liver Injury metabolism
Chemical and Drug Induced Liver Injury pathology
Cytochrome P-450 CYP2E1 genetics
Dose-Response Relationship, Drug
Injections, Intraperitoneal
Insecticides administration & dosage
Insecticides blood
Insecticides metabolism
Insecticides toxicity
Liver drug effects
Liver pathology
Male
Mice
Mice, 129 Strain
Mice, Knockout
NF-kappa B p52 Subunit metabolism
Oxidation-Reduction
Propane administration & dosage
Propane blood
Propane metabolism
Propane toxicity
Solvents administration & dosage
Solvents analysis
Solvents toxicity
Toxicokinetics
Carcinogens, Environmental metabolism
Chemical and Drug Induced Liver Injury enzymology
Cytochrome P-450 CYP2E1 metabolism
Liver metabolism
Propane analogs & derivatives
Solvents metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1477-0393
- Volume :
- 32
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Toxicology and industrial health
- Publication Type :
- Academic Journal
- Accession number :
- 25681370
- Full Text :
- https://doi.org/10.1177/0748233714568801