title: Naphthalene cytotoxicity in microsomal epoxide hydrolase deficient mice.
abstract: Naphthalene (NA) is a ubiquitous pollutant to which humans are widely exposed. 1,2-Dihydro-1,2-dihydroxynaphthalene (NA-dihydrodiol) is a major metabolite of NA generated by microsomal epoxide hydrolase (mEH). To investigate the role of the NA-dihydrodiol and subsequent metabolites (i.e. 1,2-naphthoquinone) in cytotoxicity, we exposed both male and female wild type (WT) and mEH null mice (KO) to NA by inhalation (5, 10, 20 ppm for 4h). NA-dihydrodiol was ablated in the KO mice. High-resolution histopathology was used to study site-specific cytotoxicity, and formation of naphthalene metabolites was measured by HPLC in microdissected airways. Swollen and vacuolated airway epithelial cells were observed in the intra- and extrapulmonary airways of all mice at and below the current OSHA standard (10 ppm). Female mice may be more susceptible to this acute cytotoxicity. In the extrapulmonary airways, WT mice were more susceptible to damage than KO mice, indicating that the metabolites associated with mEH-mediated metabolism could be partially responsible for cytotoxicity at this site. The level of cytotoxicity in the mEH KO mice at all airway levels suggests that non-mEH metabolites are contributing to NA cellular damage in the lung. Our results indicate that the apparent contribution of mEH-dependent metabolites to toxicity differs by location in the lung. These studies suggest that metabolites generated through the mEH pathway may be of minor importance in distal airway toxicity and subsequent carcinogenesis from NA exposure.
authors: Center for Health and the Environment, University of California Davis, Davis, CA 95616, USA.
authors: S A
authors: SA
authors: Carratt
authors: Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA.
authors: D
authors: D
authors: Morin
authors: Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA.
authors: A R
authors: AR
authors: Buckpitt
authors: Center for Health and the Environment, University of California Davis, Davis, CA 95616, USA.
authors: P C
authors: PC
authors: Edwards
authors: Center for Health and the Environment, University of California Davis, Davis, CA 95616, USA; Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA. Electronic address: lsvanwinkle@ucdavis.edu.
authors: L S
authors: LS
authors: Van Winkle
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004851:Epoxide Hydrolases / Q000172:deficiency / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D009281:Naphthalenes / Q000378:metabolism / Q000633:toxicity*; D012727:Sex Characteristics
chemical_list: D009281:Naphthalenes; C031721:naphthalene; D004851:Epoxide Hydrolases
keywords: Carcinogen metabolism; Cell injury/cell death; Cytochrome P450; HPLC; Lung/pulmonary/olfactory; Microsomal epoxide hydrolase; Toxicology