Effects of Zidovudine Treatment on Heart mRNA Expression and Mitochondrial DNA Copy Number Associated with Alterations in Deoxynucleoside Triphosphate Composition in a Neonatal Rat Model.
Effects of Zidovudine Treatment on Heart mRNA Expression and Mitochondrial DNA Copy Number Associated with Alterations in Deoxynucleoside Triphosphate Composition in a Neonatal Rat Model.
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齐多夫定治疗对新生大鼠模型中与脱氧核苷三磷酸成分改变相关的心脏 mRNA 表达和线粒体 DNA 拷贝数的影响。
DOI：
10.1128/aac.01180-15
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发表时间：
2015
影响因子：
4.9
通讯作者：
McKee,EdwardE
中科院分区：
文献类型：
--
作者：
Snowdin,JacobW;Hsiung,Chia-Heng;Kesterson,DanielG;Kamath,VasudevaG;McKee,EdwardE
预防艾滋病毒母婴传播是艾滋病毒治疗的一个关键组成部分。核苷逆转录酶抑制剂（NRTI），主要是3′-叠氮基-3 ′-胸苷（AZT [齐多夫定]），已用于治疗母亲和新生儿。虽然在预防母婴传播的治疗中，叠氮胸苷正在被毒性较低的药物所取代，但它仍然普遍用于治疗新生儿。在接受AZT治疗的队列中报告了与AZT治疗相关的线粒体毒性和潜在诱变相关的问题。然而，关于AZT对胚胎和新生儿组织的代谢和潜在毒性知之甚少，特别是考虑到核苷代谢的酶在此期间随着许多组织从增生转化为肥大生长而发生显著变化。已知AZT可抑制胸苷磷酸化，并可能改变成人的脱氧核苷三磷酸（dNTP）库。本研究在新生大鼠模型中检测AZT对dNTP池、脱氧核苷/脱氧核苷酸代谢酶mRNA表达和线粒体DNA水平的影响。结果显示，AZT治疗在出生后的前7天内显著改变了dNTP池，在第二周和第三周与年龄匹配的对照组恢复正常。此外，AZT治疗显著增加了许多酶的mRNA水平，这些酶在生命的第一周参与脱氧核苷酸合成和线粒体生物合成，到第三周时恢复正常。这些结果与第二周观察到的线粒体DNA耗竭相关。两者合计，结果表明，AZT治疗有一个强大的影响脱氧核苷酸合成途径，可能与毒性和诱变。
The prevention of mother-to-child transmission (MTCT) of HIV is a crucial component in HIV therapy. Nucleoside reverse transcriptase inhibitors (NRTIs), primarily 3′-azido-3′-thymidine (AZT [zidovudine]), have been used to treat both mothers and neonates. While AZT is being replaced with less toxic drugs in treating mothers in MTCT prevention, it is still commonly used to treat neonates. Problems related to mitochondrial toxicity and potential mutagenesis associated with AZT treatment have been reported in treated cohorts. Yet little is known concerning the metabolism and potential toxicity of AZT on embryonic and neonatal tissues, especially considering that the enzymes of nucleoside metabolism change dramatically as many tissues convert from hyperplastic to hypertrophic growth during this period. AZT is known to inhibit thymidine phosphorylation and potentially alter deoxynucleoside triphosphate (dNTP) pools in adults. This study examines the effects of AZT on dNTP pools, mRNA expression of deoxynucleoside/deoxynucleotide metabolic enzymes, and mitochondrial DNA levels in a neonatal rat model. Results show that AZT treatment dramatically altered dNTP pools in the first 7 days of life after birth, which normalized to age-matched controls in the second and third weeks. Additionally, AZT treatment dramatically increased the mRNA levels of many enzymes involved in deoxynucleotide synthesis and mitochondrial biogenesis during the first week of life, which normalized to age-matched controls by the third week. These results were correlated with depletion of mitochondrial DNA noted in the second week. Taken together, results demonstrated that AZT treatment has a powerful effect on the deoxynucleotide synthesis pathways that may be associated with toxicity and mutagenesis.