Species differences in the regio- and stereoselectivity of 1-nitronaphthalene metabolism.
Species differences in the regio- and stereoselectivity of 1-nitronaphthalene metabolism.
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发表时间：
2000-04
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通讯作者：
K. C. Watt;A. Buckpitt
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作者：
K. C. Watt;A. Buckpitt
1-硝基萘（1-NN）是一种致突变的硝基芳香族化合物，已在重型和轻型柴油发动机的排放物以及城市空气中的颗粒物中检测到。1-NN是一种细胞色素P450生物活化的无纤毛细支气管上皮（Clara）细胞毒性剂。我们最近的研究表明，1-NN被大鼠肺和肝微粒体酶代谢，通过中间体C（5），C（6）-和C（7），C（8）-环氧化物，生成6种1-NN GSH缀合物。这些研究检查了1-NN在小鼠中的代谢，并比较了两个物种之间1-NN GSH缀合物形成速率的差异。HPLC放射性图谱表明，在小鼠肺和肝微粒体孵育中生成了7种不同的结合物。7种结合物中有6种与大鼠微粒体孵育中观察到的结合物一致。当在电喷雾正离子模式下通过质谱分析时，新缀合物的质谱产生m/z 497（M+H）和与其他六种缀合物相同的子离子。小鼠和大鼠肺微粒体孵育中产生的主要结合物为结合物4（1-硝基-7-谷胱甘肽-8-羟基-7，8-二氢萘）。相比之下，缀合物6（1-硝基-5-羟基-6-谷胱甘肽-5，6-二氢萘）的形成在小鼠肝脏中占主导地位，而在大鼠肝脏中，缀合物5（缀合物6的非对映体）以最高速率产生。我们得出的结论是，区域和立体异构体的环氧化物从1-NN的形成率在靶组织和非靶组织中有很大的不同，但没有明确的模式，组织的敏感性的速率或代谢产物的相关性。
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 C(5),C(6)- and C(7),C(8)-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.