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Role of aldo-keto reductase enzymes in polycyclic aromatic hydrocarbon activation.

机译：醛酮还原酶在多环芳烃活化中的作用。

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Polycyclic aromatic hydrocarbons (PAH) are environmental pollutants and suspected human carcinogens. Cigarette smoke, considered the most important risk factor for lung cancer, contains a variety of PAH. PAH require metabolic activation to exert their deleterious effects. Aldo-keto reductases (AKR) oxidize proximate carcinogen PAH trans-dihydrodiols to catechols, which auto-oxidize forming reactive oxygen species (ROS) and o-quinones.;Fjord-region PAH are more mutagenic and carcinogenic versus unsubstituted PAH. In this study, rat AKR1C9 oxidized fjord -region benzo[g]chrysene-11,12-dihydrodiol with a kcat/Km 100-times greater than unsubstituted bay-region benzo[a]pyrene-7,8-dihydrodiol. During oxidation, only one stereoisomer was used. Alanine-scanning mutants of active site residues revealed that several active site residues enabled oxidation of both stereoisomers of benzo[g]chrysene-11,12-dihydrodiol. This suggests that AKRs may contribute to the carcinogenicity of fjord-region PAH.;One deleterious consequence of o-quinone formation is ROS generation during futile redox cycling. Consequently, ROS inflict oxidative damage to DNA. However, the identity of quinone reductases, which enhance ROS formation by reducing PAH quinones to catechols in cells, is unknown. In this study, human recombinant AKR1A1, 1B1, 1B10, 1C1-4, 7A2, 7A3, NAD(P)H quinone oxidoreductase 1 (NQ01), and carbonyl reductase (CBR) isoforms were tested as quinone reductases. Structural series of PAH o-quinones, benzo[a]pyrene diones, and estrogen replacement therapy metabolite 4-hydroxyequilenin-o-quinone were tested as substrates with each enzyme. NQO1 and the AKRs reduced all types of quinones. The specific activities with AKRs exceeded those observed for trans-dihydrodiol oxidation. CBRs reduced few PAH quinones, implying CBRs are not the major cellular quinone reductases. NQO1 had higher specific activities than AKRs. However, the Km for NADPH with NQO1 is higher than the AKRs, which could limit quinone reduction by NQO1 in cells. Contributions of AKRs and NQO1 to ROS formation in human lung adenocarcinoma A549 cells treated with PAH o-quinones with AKR1C or NQO1 inhibitors was tested. No change in ROS formation occurred with these inhibitors, suggesting that NQO1 does not reduce quinones in A549 cells. However, AKRs not blocked by the AKR1C inhibitor may play roles in quinone reduction of PAH quinones in A549 cells. This could lead to increased oxidative stress following o-quinone formation and ultimately contribute to chemical and hormonal carcinogenesis.
机译：多环芳烃（PAH）是环境污染物和可疑的人类致癌物。卷烟被认为是肺癌的最重要危险因素，其中含有多种PAH。 PAH需要代谢激活才能发挥其有害作用。醛酮还原酶（AKR）将近致癌物PAH反式二氢二醇氧化为儿茶酚，后者会自动氧化形成活性氧（ROS）和邻醌。在这项研究中，大鼠AKR1C9氧化了峡湾区的苯并[g] ch-11,12-二氢二醇，其kcat / Km比未取代的海湾区的苯并[a] py-7,8-二氢二醇大100倍。在氧化过程中，仅使用一种立体异构体。活性位点残基的丙氨酸扫描突变体表明，几个活性位点残基能够氧化苯并[g] ch-11,12-二氢二醇的两种立体异构体。这表明AKRs可能有助于峡湾区PAH的致癌性。邻醌形成的一个有害后果是在无效的氧化还原循环过程中产生了ROS。因此，ROS对DNA造成氧化损伤。然而，未知的醌还原酶通过将PAH醌还原为细胞中的儿茶酚来增强ROS的形成。在这项研究中，人类重组AKR1A1、1B1、1B10、1C1-4、7A2、7A3，NAD（P）H醌氧化还原酶1（NQ01）和羰基还原酶（CBR）同工型作为醌还原酶进行了测试。测试了PAH邻醌，苯并[a] py二酮和雌激素替代疗法的代谢产物4-羟基e烯-邻醌的结构系列与每种酶的底物。 NQO1和AKR还原所有类型的醌。 AKR的比活超过了反式二氢二醇氧化所观察到的那些。 CBR还原了很少的PAH醌，这表明CBR不是主要的细胞醌还原酶。 NQO1的比活度高于AKR。但是，带有NQO1的NADPH的Km高于AKR，这可能会限制细胞中NQO1导致的醌还原。测试了AKR和NQO1对用PAH邻醌与AKR1C或NQO1抑制剂处理的人肺腺癌A549细胞中ROS形成的贡献。这些抑制剂在ROS的形成上没有变化，表明NQO1不会还原A549细胞中的醌。但是，未被AKR1C抑制剂阻断的AKR可能在A549细胞中PAH醌的醌还原中起作用。这可能导致邻醌形成后氧化应激增加，并最终促进化学和激素致癌作用。

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