Carbonyl reductase 1 is a predominant doxorubicin reductase in the human liver
Carbonyl reductase 1 is a predominant doxorubicin reductase in the human liver
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DOI：
10.1124/dmd.108.022251
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发表时间：
2008-10-01
影响因子：
3.9
通讯作者：
Wojnowski, Leszek
中科院分区：
文献类型：
--
作者：
Kassner, Nina;Huse, Klaus;Wojnowski, Leszek
酶促处理药物阿霉素（DOX）的第一步是还原为阿霉素酚（DOX-OL）。由于DOX-OL的毒性较母体化合物低，但心脏毒性更大，因此该反应的个体发生率可能影响抗肿瘤作用和DOX诱导心力衰竭的风险。使用纯化的酶和人体组织，我们确定酶产生DOX-OL和他们的活动的个体差异。人体组织表达至少两种DOX还原酶。高清除器官（肾脏、肝脏和胃肠道）表达一种表观Km值类似于140 μ M的酶。在发现的六种减少DOX的酶中，羰基还原酶1（CBR 1）和醛酮还原酶（AKR）1C 3表现出在该范围内的K-m值。CBR 1在这三个器官中的表达水平高于AKR 1C 3，而AKR 1C 3具有更高的催化效率。
A first step in the enzymatic disposition of the antineoplastic drug doxorubicin (DOX) is the reduction to doxorubicinol (DOX-OL). Because DOX-OL is less antineoplastic but more cardiotoxic than the parent compound, the individual rate of this reaction may affect the antitumor effect and the risk of DOX-induced heart failure. Using purified enzymes and human tissues we determined enzymes generating DOX-OL and interindividual differences in their activities. Human tissues express at least two DOX-reducing enzymes. High-clearance organs (kidney, liver, and the gastrointestinal tract) express an enzyme with an apparent K-m of similar to 140 mu M. Of six enzymes found to reduce DOX, K-m values in this range are exhibited by carbonyl reductase 1 (CBR1) and aldo-keto reductase (AKR) 1C3. CBR1 is expressed in these three organs at higher levels than AKR1C3, whereas AKR1C3 has higher catalytic efficiency.