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Toxicological Sciences 53, 352-360 (2000)
Copyright © 2000 by the Society of Toxicology

Cytotoxicity of 1,2-epoxynaphthalene Is Correlated with Protein Binding and in Situ Glutathione Depletion in Cytochrome P4501A1 Expressing Sf-21 Cells

Jessica F. Greene*, Jiang Zheng{dagger}, David F. Grant{ddagger} and Bruce D. Hammock*,1

* Department of Entomology, University of California at Davis, Davis, California 95616; {dagger} Bouve College of Pharmacy and Health Sciences, Northeastern University, Boston, Massachusetts 02115; and {ddagger} Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205

Naphthalene is metabolized by several cytochrome P-450 (CYP) monooxygenases to 1,2-epoxynaphthalene. However, the subsequent interactions of the epoxide with macromolecules in the cells, and the significance of these interactions to cellular injury, are not well characterized. Additionally, CYP1A1, which can metabolize naphthalene to 1,2-epoxynaphthalene, may be induced by a number of xenobiotics. Yet, the in situ interaction between naphthalene and CYP1A1 alone, without the influence of other xenobiotic metabolizing enzymes, has not been examined. Using a model eukaryotic expression system capable of over-expressing recombinant CYP1A1, we found that naphthalene was toxic to cells expressing CYP1A1 in a dose- (LC50: 0.3 mM) and time-dependent (LT50: 12 h) manner. Naphthalene treatment of CYP1A1-expressing cells resulted in a 47% decrease in cellular glutathione (GSH) levels. Pretreatment with ethyl ester GSH, a GSH analog, protected CYP1A1-expressing cells such that viability was 30% greater than for cells treated with naphthalene alone. Cytotoxicity was strongly correlated (r2: 0.96) with covalent binding of cellular proteins. Alkaline permethylation techniques showed that cysteinyl-SH groups of cellular proteins are a nucleophilic target of the epoxide metabolite. These results suggest that, in the absence of other pathways, naphthalene is modified by CYP1A1 to 1,2-epoxynaphthalene, which subsequently binds cellular sulfhydryl groups on proteins and GSH.

Key Words: 1,2-epoxynaphthalene; naphthalene; glutathione; ethyl ester glutathione; CYP1A1; Sf-21; alkaline permethylation.


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