1-Nitronaphthalene (1-NN) is a mutagenic nitroaromatic that has been detected in emissions from both heavy- and light-duty diesel engines, as well as in urban airborne particles. 1-NN is a cytochrome P450-bioactivated, nonciliated bronchiolar epithelial (Clara) cell cytotoxicant. Our recent studies demonstrated that 1-NN was metabolized by rat lung and liver microsomal enzymes to six 1-NN GSH conjugates via intermediate C5,C6- and C7,C8-epoxides. These studies examined the metabolism of 1-NN in mouse, and compared the differences in rates of 1-NN GSH conjugate formation between the two species. HPLC radioactivity profiles demonstrated that seven different conjugates were generated in mouse lung and liver microsomal incubations. Six of the seven conjugates corresponded with those observed in incubations with rat microsomes. Mass spectrometry of the new conjugate yielded a m/z 497 (M+H) and identical daughter ions as in the other six conjugates when analyzed by mass spectrometry in electrospray positive ion mode. The major conjugate generated in mouse and rat lung microsomal incubations was conjugate 4 (1-nitro-7-glutathionyl-8-hydroxy-7,8-dihydronaphthalene). In comparison, the formation of conjugate 6 (1-nitro-5-hydroxy-6-glutathionyl- 5,6-dihydronaphthalene) predominated in mouse liver, whereas in rat liver, conjugate 5, a diastereomer of conjugate 6, was generated at the highest rate. We concluded that the rates of formation of regio- and stereoisomeric epoxides from 1-NN differed substantially in target and nontarget tissues, but there was no clear pattern of correlation of tissue susceptibility to the rate or metabolite produced.
|Original language||English (US)|
|Number of pages||3|
|Journal||Drug Metabolism and Disposition|
|State||Published - 2000|
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