来自AKR1C亚家族的Aldo-酮基还原酶（AKR）催化人体内新型抗癌药物oracin的羰基还原。,Toxicology

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来自AKR1C亚家族的Aldo-酮基还原酶（AKR）催化人体内新型抗癌药物oracin的羰基还原。
Toxicology ( IF 4.8 ) Pub Date : 2007-07-10 , DOI: 10.1016/j.tox.2007.05.021
Vladimir Wsol ₁ , Barbora Szotakova , Hans-Joerg Martin , Edmund Maser

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在许多情况下，癌症化学疗法的反应率仍不令人满意，罕见的完全缓解和持续时间相对较短的反应。因此，不断寻求具有新结构的抗癌药物。Oracin，6- [2-（2-羟乙基）-氨基乙基] -5,11-dioxo-5,6-dihydro-11H-indeno [1,2-c]异喹啉，是一种新的抗癌药物，目前处于阶段二，临床试验。药代动力学研究表明，oracin通过羰基还原而发生代谢失活。由于代谢失活会导致化疗耐药，因此必须详细了解参与的酶。在本研究中，我们确定了醛糖酮还原酶（AKR）超家族的三个成员，以介导人类中的oracin羰基还原。对于从人肝细胞溶质中纯化的AKR1C1、1C2和1C4，我们可以确定动力学和催化效率。此外，我们研究了还原素蛋白（DHO）形成的立体特异性。尽管AKR1C2和1C4仅对（+）-DHO形成具有立体特异性（100％），但发现AKR1C1约占（-）-DHO形成的3％。另一方面，相比于AKR1C2和1C4，AKR1C1总体上减少牛尿素的活性高一个数量级。关于oracin解毒中涉及的所有酶的详细知识可能有助于通过共同应用相应的抑制剂来改善抗癌方案。另一方面，相比于AKR1C2和1C4，AKR1C1总体上减少牛尿素的活性高一个数量级。关于oracin解毒中涉及的所有酶的详细知识可能有助于通过共同应用相应的抑制剂来改善抗癌方案。另一方面，相比于AKR1C2和1C4，AKR1C1总体上减少牛尿素的活性高一个数量级。关于oracin解毒中涉及的所有酶的详细知识可能有助于通过共同应用相应的抑制剂来改善抗癌方案。

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Aldo-keto reductases (AKR) from the AKR1C subfamily catalyze the carbonyl reduction of the novel anticancer drug oracin in man.

In many cases, cancer chemotherapy still obtains unsatisfactory response rates, rare complete remissions and responses of relatively short duration. Therefore, more effective drugs with new structures against cancer are continuously sought. Oracin, 6-[2-(2-hydroxyethyl)-aminoethyl]-5,11-dioxo-5,6-dihydro-11H-indeno[1,2-c]isoquinoline, is a new anticancer drug which is presently in phase II clinical trials. Pharmacokinetic studies have revealed that oracin undergoes metabolic inactivation by carbonyl reduction. Since metabolic inactivation contributes to chemotherapy resistance, detailed knowledge about the participating enzymes is necessary. In the present study, we identified three members of the aldo-keto reductase (AKR) superfamily to mediate oracin carbonyl reduction in man. For AKR1C1, 1C2 and 1C4, purified from human liver cytosol, we could determine the kinetics and catalytic efficiencies. In addition, we investigated the stereospecificity of formation of reduced oracin (DHO). Whereas AKR1C2 and 1C4 are exclusively (100%) stereospecific for (+)-DHO formation, some 3% of (-)-DHO formation was found for AKR1C1. On the other hand, the activity of AKR1C1 in overall oracin reduction was one order of magnitude higher compared to AKR1C2 and 1C4. Detailed knowledge about all enzymes involved in oracin detoxification may help to improve an anticancer regimen by co-application of respective inhibitors.

更新日期：2019-11-01

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