Chae Y H, Thomas T, Guengerich F P, Fu P P, El-Bayoumy K
Division of Cancer Etiology and Prevention, American Health Foundation, Valhalla, New York 10595, USA.
Cancer Res. 1999 Apr 1;59(7):1473-80.
Determining the capability of humans to metabolize the mononitropyrene (mono-NP) isomers 1-, 2-, and 4-NP and understanding which human cytochrome P450 (P450) enzymes are involved in their activation and/or detoxification is important in the assessment of individual susceptibility to these environmental carcinogens. We compared the ability of 15 human hepatic and 8 pulmonary microsomal samples to metabolize each of the three isomers. Human hepatic microsomes were competent in metabolizing all three isomers. Qualitatively similar metabolic patterns were observed, although at much lower levels, upon incubating mono-NP with pulmonary microsomes. Ring-oxidized metabolites (phenols and trans-dihydrodiols) were produced from all three isomers. However, the nitroreductive metabolism leading to the formation of aminopyrene was evident only with 4-NP. The role of specific P450 enzymes in the human hepatic microsomal metabolism of mono-NP was investigated by correlating the P450-dependent catalytic activities in each microsomal sample with the levels of individual metabolites formed by the same microsomes and by examining the effects of agents that can either inhibit or stimulate specific P450 enzymes in mono-NP metabolism. On the basis of these studies, we attribute most of the hepatic microsomal metabolism of 1- and 4-NP to P450 3A4, although a minor role for P450 1A2 cannot be ruled out. Specifically, P450 3A4 was responsible for the formation of 3-hydroxy-1nitropyrene from 1-NP and the formation of trans-9,10-dihydro-9,10dihydroxy-4-nitropyrene, 9(10)-hydroxy-4-nitropyrene, and 4-aminopyrene from 4-NP. None of the P450 enzymes examined (P450s 3A4, 1A2, 2E1, 2A6, 2D6, and 2C9) appeared to be involved in catalyzing the formation of trans-4,5-dihydro-4,5-dihydroxy-2-nitropyrene and 6-hydroxy-2-nitropyrene from 2-NP in human hepatic microsomes. These results, the first report on the comparative metabolism of mono-NP in humans, clearly demonstrate that the role of specific human P450 enzymes in catalyzing oxidative and reductive pathways of mono-NP is dependent upon the position of the nitro group.
确定人类代谢单硝基芘（单-NP）异构体1-、2-和4-NP的能力，并了解哪些人细胞色素P450（P450）酶参与其激活和/或解毒，对于评估个体对这些环境致癌物的易感性很重要。我们比较了15个人肝微粒体样品和8个人肺微粒体样品代谢这三种异构体的能力。人肝微粒体能够代谢所有三种异构体。在用肺微粒体孵育单-NP时，观察到了定性相似的代谢模式，尽管水平要低得多。所有三种异构体都产生了环氧化代谢物（酚类和反式二氢二醇）。然而，仅4-NP能明显观察到导致氨基芘形成的硝基还原代谢。通过将每个微粒体样品中P450依赖的催化活性与同一微粒体形成的单个代谢物水平相关联，并通过研究可抑制或刺激单-NP代谢中特定P450酶的试剂的作用，研究了特定P450酶在人肝微粒体单-NP代谢中的作用。基于这些研究，我们将1-NP和4-NP的大部分肝微粒体代谢归因于P450 3A4，尽管不能排除P450 1A2的次要作用。具体而言，P450 3A4负责由1-NP形成3-羟基-1-硝基芘，以及由4-NP形成反式-9,10-二氢-9,10-二羟基-4-硝基芘、9(10)-羟基-4-硝基芘和4-氨基芘。在所检测的P450酶（P450 3A4、1A2、2E1、2A6、2D6和2C9）中，似乎没有一种参与催化人肝微粒体中由2-NP形成反式-4,5-二氢-4,5-二羟基-2-硝基芘和6-羟基-2-硝基芘。这些结果是关于单-NP在人体内比较代谢的首次报道，清楚地表明特定人P450酶在催化单-NP氧化和还原途径中的作用取决于硝基的位置。
