Role of Pyrimidine Depletion in the Mitochondrial Cardiotoxicity of Nucleoside Analogue Reverse Transcriptase Inhibitors
Role of Pyrimidine Depletion in the Mitochondrial Cardiotoxicity of Nucleoside Analogue Reverse Transcriptase Inhibitors
复制标题
嘧啶消耗在核苷类似物逆转录酶抑制剂线粒体心脏毒性中的作用
DOI：
10.1097/qai.0b013e3181f25946
复制
发表时间：
2010
期刊：
影响因子：
--
通讯作者：
UA. Walker
中科院分区：
文献类型：
--
作者：
K. Balcarek;D. Lebrecht;C. Deveaud;B. Beauvoid;J. Bonnet;JB. Kirschner;N. Venhoff;UA. Walker
目的：核苷类似物逆转录酶抑制剂（NRTI）长期抗逆转录病毒治疗可能导致线粒体DNA（mtDNA）耗竭导致心肌病。完整的线粒体功能是合成心肌内嘧啶核苷酸所必需的，而嘧啶核苷酸又是线粒体DNA的构建模块。我们调查了NRTI相关的心肌病是否可以预防与嘧啶precurs.Methods：小鼠与齐多夫定或扎西他滨喂养或不同时Mitocnol，膳食补充剂具有高尿苷生物利用度。结果：两种NRTI均诱发心肌病，电镜下心肌线粒体增大，嵴结构紊乱，线粒体DNA拷贝数减少。心肌线粒体DNA编码的细胞色素c氧化酶I亚基比细胞核编码的细胞色素c氧化酶IV亚基受损更严重。在齐多夫定和扎西他滨治疗的动物中，活性氧和线粒体DNA突变的心肌形成增强。Mitocnol衰减或正常化的所有心肌病变时，都NRTI，但本身没有内在的影响，没有明显的不良反应。结论：齐多夫定和扎西他滨诱导线粒体心肌病，这是拮抗补充尿苷，牵连嘧啶池耗尽其发病机制。由于尿苷耐受性良好，因此可在临床上利用嘧啶库补充。
Objective:Long-term antiretroviral treatment with nucleoside analogue reverse transcriptase inhibitors (NRTI) may result in a cardiomyopathy due to mitochondrial DNA (mtDNA) depletion. An intact mitochondrial function is required for the synthesis of intramyocardial pyrimidine nucleotides, which in turn are building blocks of mtDNA. We investigated if NRTI-related cardiomyopathy can be prevented with pyrimidine precursors.Methods:Mice were fed with zidovudine or zalcitabine with or without simultaneous Mitocnol, a dietary supplement with high uridine bioavailability. Myocardia were examined after 9 weeks.Results:Both NRTI induced a cardiomyopathy with mitochondrial enlargement, a disrupted cristal architecture on electron microscopy and diminished myocardial mtDNA copy numbers. The myocardial mtDNA-encoded cytochrome c-oxidase I subunit was impaired more profoundly than the nucleus-encoded cytochrome c-oxidase IV subunit. The myocardial formation of reactive oxygen species and mtDNA mutations was enhanced in zidovudine and zalcitabine treated animals. Mitocnol attenuated or normalized all myocardial pathology when given with both NRTI, but by itself had no intrinsic effects and no apparent adverse effects.Conclusions:Zidovudine and zalcitabine induce a mitochondrial cardiomyopathy, which is antagonized with uridine supplementation, implicating pyrimidine pool depletion in its pathogenesis. Pyrimidine pool replenishment may be exploited clinically because uridine is well tolerated.
登录
查看更多内容
尿苷消除 Hepg2 细胞中与核苷类似物逆转录酶抑制剂相关的线粒体毒性
影响因子：
1.2
作者：
U. Walker;N. Venhoff;E. C. Koch;M. Olschewski;Josef Schneider;B. Setzer
通讯作者：
B. Setzer
影响因子：
5
作者：
Lewis, William;Day, Brian J.;Copeland, William C.
通讯作者：
Copeland, William C.
影响因子：
56.9
作者：
SCHON, EA;RIZZUTO, R;DIMAURO, S
通讯作者：
DIMAURO, S
DOI：
10.1001/jama.1991.03470130092035
发表时间：
1991-10
期刊：
JAMA
影响因子：
--
作者：
M. Corral‐Debrinski;G. Stepien;J. Shoffner;M. Lott;K. Kanter;D. Wallace
通讯作者：
M. Corral‐Debrinski;G. Stepien;J. Shoffner;M. Lott;K. Kanter;D. Wallace
影响因子：
13.5
作者：
U. Walker;J. Bäuerle;M. Laguno;J. Murillas;S. Mauss;G. Schmutz;B. Setzer;R. Miquel;J. Gatell;J. Mallolas
通讯作者：
U. Walker;J. Bäuerle;M. Laguno;J. Murillas;S. Mauss;G. Schmutz;B. Setzer;R. Miquel;J. Gatell;J. Mallolas