Oxidation of PAH trans-dihydrodiols by human aldo-keto reductase AKR1B10.
Oxidation of PAH trans-dihydrodiols by human aldo-keto reductase AKR1B10.
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人醛酮还原酶 AKR1B10 氧化 PAH 反式二氢二醇。
DOI：
10.1021/tx8002005
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发表时间：
2008-11
影响因子：
4.1
通讯作者：
Penning, Trevor M.
中科院分区：
文献类型：
--
作者：
Quinn, Amy M.;Harvey, Ronald G.;Penning, Trevor M.
AKR 1B 10已被确定为人类非小细胞肺癌的潜在生物标志物，并作为烟草暴露和反应基因。AKR 1B 10在体外作为一种有效的视网膜还原酶发挥作用，并可调节视黄酸稳态。然而，这种酶能够激活多环芳烃（PAH）反式二氢二醇，形成反应性和氧化还原活性的邻醌的可能性还没有调查到目前为止。AKR 1B 10被发现在体外氧化多种PAH反式二氢二醇底物，产生PAH邻醌。AKR 1B 10的反应以不适当的立体化学进行，因为它对体内形成的次要（+）-苯并[a]芘-7S，8 S-二氢二醇非对映体具有特异性。然而，AKR 1B 10在苯并[g]蒽-11，12-二氢二醇的（−）-R，R和（+）-S，S立体异构体的氧化中显示出合理的活性，并氧化了潜在相关的（+）-苯并[a]蒽-3S，4S-二氢二醇代谢物，尽管是次要的。因此，我们发现AKR 1B 10可能在人肺中PAH trans-dihydrodioles的激活中起作用。AKR 1B 10视网膜还原酶活性在体外得到证实，发现比所检测的PAH反式二氢二醇的氧化高5- 150倍。AKR 1B 10在人肺腺癌A549细胞中在mRNA和蛋白水平上高度表达，并且在这些细胞的裂解物中测量到稳健的视网膜还原酶活性。与PAH反式二氢二醇代谢相比，视黄醇还原的催化效率更高，表明AKR 1B 10可能通过维甲酸稳态失调而不是通过PAH反式二氢二醇氧化在肺癌发生中发挥更大的作用。
AKR1B10 has been identified as a potential biomarker for human non-small cell lung carcinoma and as a tobacco exposure and response gene. AKR1B10 functions as an efficient retinal reductase in vitro, and may regulate retinoic acid homeostasis. However, the possibility that this enzyme is able to activate polycyclic aromatic hydrocarbon (PAH) trans-dihydrodiols to form reactive and redox-active o-quinones has not been investigated to date. AKR1B10 was found to oxidize a wide range of PAH trans-dihydrodiol substrates in vitro to yield PAH o-quinones. Reactions of AKR1B10 proceeded with improper stereochemistry, since it was specific for the minor (+)-benzo[a]pyrene-7S,8S-dihydrodiol diastereomer formed in vivo. However, AKR1B10 displayed reasonable activity in the oxidation of both the (−)-R,R and (+)-S,S stereoisomers of benzo[g]chrysene-11,12-dihydrodiol and oxidized the potentially relevant, albeit minor, (+)-benz[a]anthracene-3S,4S-dihydrodiol metabolite. We find that AKR1B10 is therefore likely to play a contributing role in the activation of PAH trans-dihydrodiols in human lung. AKR1B10 retinal reductase activity was confirmed in vitro and found to be 5- to 150-fold greater than the oxidation of PAH trans-dihydrodiols examined. AKR1B10 was highly expressed at the mRNA and protein levels in human lung adenocarcinoma A549 cells, and robust retinal reductase activity was measured in lysates of these cells. The much greater catalytic efficiency of retinal reduction compared to PAH trans-dihydrodiol metabolism suggests AKR1B10 may play a greater role in lung carcinogenesis through dysregulation of retinoic acid homeostasis than through oxidation of PAH trans-dihydrodiols.
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影响因子：
4.1
作者：
Jiang, H;Shen, YM;Penning, TM
通讯作者：
Penning, TM
影响因子：
11.2
作者：
Kim, Bumjin;Lee, Hyun Joo;Lee, Sanghyuk
通讯作者：
Lee, Sanghyuk
影响因子：
11.4
作者：
DETHE, H;MARCHIO, A;DEJEAN, A
通讯作者：
DEJEAN, A
影响因子：
11.5
作者：
Fukumoto, S;Yamauchi, N;Aburatani, H
通讯作者：
Aburatani, H
影响因子：
4.7
作者：
Brabender, J;Metzger, R;Schneider, PM
通讯作者：
Schneider, PM