Chae Y H, Yun C H, Guengerich F P, Kadlubar F F, el-Bayoumy K
Division of Chemical Carcinogenesis, American Health Foundation, Valhalla, New York 10595.
Cancer Res. 1993 May 1;53(9):2028-34.
6-Nitrochrysene is remarkably tumorigenic in the lung and liver of newborn mice and approximates the activities of certain ultimate carcinogenic metabolites of polycyclic aromatic hydrocarbons. Previous studies have indicated that the major metabolic activation pathway of 6-nitrochrysene in newborn mice is initially through the formation of the proximate tumorigen trans-1,2-dihydro-1,2-dihydroxy-6-aminochrysene with subsequent formation of 1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-6-aminochrysene. In order to provide information on the possible risk associated with human exposure to 6-nitrochrysene, the ability of human hepatic and pulmonary microsomes to metabolize 6-nitrochrysene was investigated. The major metabolites identified in 11 hepatic microsomes were trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene, trans-9,10-dihydro-9,10-dihydroxy-6-nitrochrysene, trans-1,2-dihydro-1,2-dihydroxy-6-aminochrysene, 6-aminochrysene, and chrysene-5,6-quinone. Following the incubations of 6-nitrochrysene with 11 different human pulmonary microsomes, qualitatively similar metabolic patterns were obtained, although quantitative differences were evident. These results demonstrated that human liver and lung are capable of metabolizing 6-nitrochrysene to known potent carcinogenic metabolites via ring oxidation and nitroreduction. In an attempt to define the roles of individual human hepatic P450 involved in the metabolism of 6-nitrochrysene, the catalytic activities known to be associated with a specific P450 were analyzed and compared with the levels of each metabolite of 6-nitrochrysene formed with the same microsomes. Rates of phenacetin O-deethylation (P450 1A2) and nifedipine oxidation (P450 3A4) were well correlated with the rates of formation of trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene and 6-aminochrysene, respectively. Inhibition studies with specific P450 inhibitors and antibodies further support the view that P450 1A2 and P450 3A4 are the major forms responsible for the formation of trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene and 6-aminochrysene, respectively, in human liver. Further metabolism of trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene appears to require P450 3A4. In the human lung, P450 1A1 appears to play a major role in the metabolism of 6-nitrochrysene to trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene. These results provide some requisite knowledge for evaluating human susceptibility to 6-nitrochrysene.
6-硝基屈对新生小鼠的肺和肝脏具有显著的致癌性，其致癌活性与某些多环芳烃的最终致癌代谢物相近。先前的研究表明，新生小鼠体内6-硝基屈的主要代谢活化途径最初是通过形成近端致癌物质反式-1,2-二氢-1,2-二羟基-6-氨基屈，随后形成1,2-二羟基-3,4-环氧-1,2,3,4-四氢-6-氨基屈。为了提供有关人类接触6-硝基屈可能产生的风险的信息，研究了人肝微粒体和肺微粒体代谢6-硝基屈的能力。在11种肝微粒体中鉴定出的主要代谢物为反式-1,2-二氢-1,2-二羟基-6-硝基屈、反式-9,10-二氢-9,10-二羟基-6-硝基屈、反式-1,2-二氢-1,2-二羟基-6-氨基屈、6-氨基屈和屈-5,6-醌。在用6-硝基屈与11种不同的人肺微粒体孵育后，虽然存在明显的定量差异，但获得了定性相似的代谢模式。这些结果表明，人肝脏和肺能够通过环氧化和硝基还原将6-硝基屈代谢为已知的强效致癌代谢物。为了确定参与6-硝基屈代谢的个体人肝P450的作用，分析了已知与特定P450相关的催化活性，并与用相同微粒体形成的6-硝基屈的每种代谢物的水平进行了比较。非那西丁O-脱乙基化（P450 1A2）和硝苯地平氧化（P450 3A4）的速率分别与反式-1,2-二氢-1,2-二羟基-6-硝基屈和6-氨基屈的形成速率密切相关。用特异性P450抑制剂和抗体进行的抑制研究进一步支持了以下观点：P450 1A2和P450 3A4分别是人肝脏中负责形成反式-1,2-二氢-1,2-二羟基-6-硝基屈和6-氨基屈的主要形式。反式-1,2-二氢-1,2-二羟基-6-硝基屈的进一步代谢似乎需要P450 3A4。在人肺中，P450 1A1似乎在6-硝基屈代谢为反式-1,2-二氢-1,2-二羟基-6-硝基屈过程中起主要作用。这些结果为评估人类对6-硝基屈的易感性提供了一些必要的知识。
