3′-azido-3′-deoxythymidine (AZT) is a competitive inhibitor of thymidine phosphorylation in isolated rat heart and liver mitochondria
3′-azido-3′-deoxythymidine (AZT) is a competitive inhibitor of thymidine phosphorylation in isolated rat heart and liver mitochondria
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DOI：
10.1016/j.bcp.2006.04.004
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发表时间：
2006-07-14
影响因子：
5.8
通讯作者：
McKee, Edward E.
中科院分区：
文献类型：
--
作者：
Lynx, Matthew D.;McKee, Edward E.
长期使用3 '-叠氮基-3'-脱氧胸苷（AZT）与各种组织毒性相关，包括肝毒性和心肌病，以及线粒体DNA耗竭。AZT-5 '-三磷酸（AZTTP）是一种已知的线粒体DNA聚合酶γ抑制剂，并已被靶向为线粒体DNA耗竭的来源。然而，在本实验室先前对分离的大鼠心脏和肝脏线粒体的研究中，AZT本身被证明是胸苷磷酸化的更有效的抑制剂（心脏线粒体中7.0 +/- 1.0 μ M AZT和肝脏线粒体中14.4 +/- 2.6 μ M AZT的IC 50）比AZTTP的聚合酶γ（IC 50> 100 μ M AZTTP），表明TTP的线粒体储存的消耗可能限制复制，并可能是在受AZT毒性影响的组织中观察到的线粒体DNA消耗的原因。这项工作的目的是表征的性质AZT抑制胸苷磷酸化在离体大鼠心脏和大鼠肝脏线粒体。在这两种组织中，发现AZT是胸苷激酶2催化的胸苷磷酸化为TMP的竞争性抑制剂。心脏线粒体的抑制常数（Ki）为10.6 +/- 4.5 μ M AZT，肝脏线粒体的Ki为14.0 +/- 2.5 μ M AZT。由于AZT是一种竞争性抑制剂，增加胸苷浓度可能是克服死亡抑制和降低AZT相关毒性的一种机制。(c)2006年爱思唯尔公司All rights reserved.
Long-term use of 3'-azido-3'-deoxythymidine (AZT) is associated with various tissue toxicities, including hepatotoxicity and cardiomyopathy, and with mitochondrial DNA depletion. AZT-5'-triphosphate (AZTTP) is a known inhibitor of the mitochondrial DNA polymerase gamma and has been targeted as the source of the mitochondrial DNA depletion. However, in previous work from this laboratory with isolated rat heart and liver mitochondria, AZT itself was shown to be a more potent inhibitor of thymidine phosphorylation (IC50 of 7.0 +/- 1.0 mu M AZT in heart mitochondria and of 14.4 +/- 2.6 mu M AZT in liver mitochondria) than AZTTP is of polymerase gamma (IC50 of > 100 mu M AZTTP), suggesting that depletion of mitochondrial stores of TTP may limit replication and could be the cause of the mitochondrial DNA depletion observed in tissues affected by AZT toxicity. The purpose of this work is to characterize the nature of AZT inhibition of thymidine phosphorylation in isolated rat heart and rat liver mitochondria. In both of these tissues, AZT was found to be a competitive inhibitor of the phosphorylation of thymidine to TMP, catalyzed by thymidine kinase 2. The inhibition constant (K-i) for heart mitochondria is 10.6 +/- 4.5 mu M AZT, and for liver mitochondria K-i is 14.0 +/- 2.5 mu M AZT. Since AZT is functioning as a competitive inhibitor, increasing thymidine concentrations may be one mechanism to overcome die inhibition and decrease AZT-related toxicity in these tissues. (c) 2006 Elsevier Inc. All rights reserved.