Quantification of individual glutathione S-transferase isozymes in hepatic and pulmonary tissues of naphthalene-tolerant mice.
Acute exposure to naphthalene produces severe bronchiolar epithelial cell necrosis in mice, whereas subchronic exposure to naphthalene (200 mg/kg/7 days) fails to produce epithelial necrosis and renders the animals tolerant to subsequent challenge doses of naphthalene. Mechanisms responsible for the development of tolerance have not been delineated. The few studies exploring naphthalene tolerance focus on expression of microsomal enzymes and have yet to delve into expression of the hepatic detoxification enzymes such as glutathione S-transferases (GSTs; EC 2.5.1.18). Glutathione conjugation catalyzed by GSTs accounts for one of the two primary routes of naphthalene detoxification. In this study, we rigorously quantify levels of individual GST isozymes expressed within the livers and lungs of mice with acquired tolerance to naphthalene. Subchronic exposure to naphthalene increases the abundance of some hepatic GSTs to levels as much as 68% greater than controls. Naphthalene-tolerant mice displayed increases in mGSTM1 (51%), mGSTM2 (58%), and mGSTP1 (66%), whereas no significant difference in mGSTA3 was observed between exposed and control mice. Extracts of pulmonary tissues from naphthalene-tolerant mice showed minor increases in levels of mGSTP1 (7%) and Peak 8 isozyme (27%) and decreases in levels of mGSTM1 (31%), mGSTM2 (17%), and mGSTA3 (8%). The total enzymatic activity for the conjugation of 1-chloro-2,4-dinitrobenzene (CDNB) was 22% lower in lung extracts from naphthalene-tolerant animals than in controls. These results indicate that induction of hepatic GSTs is substantial and may be an important factor in the development of tolerance to naphthalene.
Mitchell
A E
AE
Facility for Advanced Instrumentation, University of California, Davis 95616-8597, USA. aemitchell@ucdavis.edu
Lakritz
J
J
Jones
A D
AD
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003314:Corn Oil; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005982:Glutathione Transferase / Q000032:analysis* / Q000096:biosynthesis / Q000378:metabolism; D007527:Isoenzymes / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008168:Lung / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051379:Mice; D009281:Naphthalenes / Q000633:toxicity*; D021241:Spectrometry, Mass, Electrospray Ionization
D007527:Isoenzymes; D009281:Naphthalenes; C031721:naphthalene; D003314:Corn Oil; D005982:Glutathione Transferase