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Human aldo-keto reductases and the metabolic activation of polycyclic aromatic hydrocarbons

机译：人醛酮还原酶与多环芳烃的代谢活化

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摘要

Aldo-keto reductases (AKRs) are promiscuous NAD(P)(H) dependent oxidoreductases implicated in the metabolic activation of polycyclic aromatic hydrocarbons (PAH). These enzymes catalyze the oxidation of non-K-region trans-dihydrodiols to the corresponding o-quinones with the concomitant production of reactive oxygen species (ROS). The PAH o-quinones are Michael acceptors and can form adducts but are also redox-active and enter into futile redox cycles to amplify ROS formation. Evidence exists to support this metabolic pathway in humans. The human recombinant AKR1A1 and AKR1C1-AKR1C4 enzymes all catalyze the oxidation of PAH trans-dihydrodiols to PAH o-quinones. Many human AKRs also catalyze the NADPH-dependent reduction of the o-quinone products to air-sensitive catechols, exacerbating ROS formation. Moreover, this pathway of PAH activation occurs in a panel of human lung cell lines, resulting in the production of ROS and oxidative DNA damage in the form of 8-oxo-2′-deoxyguanosine. Using stable-isotope dilution liquid chromatography tandem mass spectrometry, this pathway of benzo[a]pyrene (B[a]P) metabolism was found to contribute equally with the diol-epoxide pathway to the activation of this human carcinogen in human lung cells. Evaluation of the mutagenicity of anti-B[a]P-diol epoxide with B[a]P-7,8-dione on p53 showed that the o-quinone produced by AKRs was the more potent mutagen, provided that it was permitted to redox cycle, and that the mutations observed were G to T transversions, reminiscent of those observed in human lung cancer. It is concluded that there is sufficient evidence to support the role of human AKRs in the metabolic activation of PAH in human lung cell lines and that they may contribute to the causation of human lung cancer.
机译：醛基酮还原酶（AKRs）是混杂的NAD（P）（H）依赖性氧化还原酶，与多环芳烃（PAH）的代谢活化有关。这些酶催化非K区反式二氢二醇氧化为相应的邻醌，同时产生活性氧（ROS）。 PAH邻醌是迈克尔受体，可以形成加合物，但也具有氧化还原活性，并进入徒劳的氧化还原循环以放大ROS的形成。有证据支持人类的这种新陈代谢途径。人重组AKR1A1和AKR1C1-AKR1C4酶均催化PAH反式二氢二醇氧化为PAH邻醌。许多人类AKR还催化NADPH依赖性的邻醌产物还原为对空气敏感的邻苯二酚，加剧了ROS的形成。此外，PAH激活的这种途径发生在一组人类肺细胞系中，从而导致ROS的产生和8-oxo-2'-脱氧鸟苷形式的氧化DNA损伤。使用稳定同位素稀释液相色谱串联质谱法，发现苯并[a] py（B [a] P）代谢的这种途径与二醇-环氧途径对人类肺细胞中这种人类致癌物的活化具有同等作用。用p [53]上的B [a] P-7,8-dione对抗B [a] P-二醇环氧化物的致突变性评估表明，只要允许，AKRs产生的邻醌是更有效的诱变剂。氧化还原循环，并且观察到的突变是从G到T的转变，让人联想到在人类肺癌中观察到的突变。结论是，有足够的证据支持人类AKR在人类肺细胞系中PAH的代谢活化中的作用，并且它们可能有助于人类肺癌的成因。

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