Characterization of enzymes participating in carbonyl reduction of 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) in human placenta
Characterization of enzymes participating in carbonyl reduction of 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) in human placenta
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DOI：
10.1016/s0009-2797(00)00304-5
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发表时间：
2001-01-30
影响因子：
5.1
通讯作者：
Maser, E
中科院分区：
文献类型：
--
作者：
Atalla, A;Maser, E
甲基亚硝胺1-（3-吡啶基）-1-丁酮（NNK）是烟草制品中最强的亚硝胺致癌物之一。羰基还原为4-甲基亚硝胺基-1-（3-吡啶基）-1-丁醇（NNAL），随后进行葡萄糖醛酸基化被认为是人体的主要解毒途径。在以前的研究中，我们已经确定了微粒体NNK羰基还原酶与11 β-羟基类固醇脱氢酶1相同，11 β-羟基类固醇脱氢酶1是短链脱氢酶/还原酶（SDR）超家族的成员。最近，我们提供的证据表明，羰基还原NNK也发生在细胞溶质从小鼠和人的肝脏和肺。在人肝胞质溶胶中，羰基还原酶（SDR酶）和醛酮还原酶（AKR）超家族的AKR 1C 1、AKR 1C 2和AKR 1C 4被证明负责NNK还原。由于NNK和/或其代谢产物可以通过胎盘扩散并到达胎儿组织，我们现在研究了除了微粒体中的NNK羰基还原外，人胎盘胞质组分中的NNK羰基还原。从对甲萘醌、依他尼酸、芦丁和槲皮苷作为特异性抑制剂的敏感性得出结论，在人胎盘胞质溶胶中似乎主要是羰基还原酶（EC1.1.1.184）进行该反应。通过RT-PCR证实羰基还原酶的存在。这是第一份报告提供证据表明，NNAL的形成在胎盘介导的羰基还原酶。(C)2001爱思唯尔科学爱尔兰有限公司保留所有权利。
dr-Methylnitrosamino 1-(3-pyridyl)-1-butanone (NNK) has been identified as one of the strongest nitrosamine carcinogens in tobacco products in all species tested. Carbonyl reduction to 4-methylnitrosamino-1-(3-pyridyl)-1-butanol (NNAL) followed by glucuronosylation is considered to be the main detoxification pathway in humans. In previous investigations, we have identified a microsomal NNK carbonyl reductase as being identical to 11 beta -hydroxysteroid dehydrogenase 1, a member of the short-chain dehydrogenase/reductase (SDR) superfamily. Recently, we provided evidence that carbonyl reduction of NNK does also take place in cytosol from mouse and human liver and lung. In human liver cytosol, carbonyl reductase, a SDR enzyme, and AKR1C1, AKR1C2 and AKR1C4 from the aldo-keto reductase (AKR) superfamily were demonstrated to be responsible for NNK reduction. Since NNK and/or its metabolites can diffuse through the placenta and reach fetal tissues, we now investigated NNK carbonyl reduction in the cytosolic fraction of human placenta in addition to that in microsomes. Concluding from the sensitivity to menadione, ethacrynic acid, rutin and quercitrin as specific inhibitors, mainly carbonyl reductase (EC 1.1.1.184) seems to perform this reaction in human placenta cytosol. The presence of carbonyl reductase was confirmed by RT-PCR. This is the first report to provide evidence that NNAL formation in placenta is mediated by carbonyl reductase. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.