Plasma and cellular markers of 3'-azido-3'-dideoxythymidine (AZT) metabolism as indicators of DNA damage in cord blood mononuclear cells from infants receiving prepartum NRTIs.
Plasma and cellular markers of 3'-azido-3'-dideoxythymidine (AZT) metabolism as indicators of DNA damage in cord blood mononuclear cells from infants receiving prepartum NRTIs.
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3-叠氮基-3-二脱氧胸苷 (AZT) 代谢的血浆和细胞标记物作为接受产前 NRTI 的婴儿脐带血单核细胞 DNA 损伤的指标。
DOI：
10.1002/em.20298
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发表时间：
2007
影响因子：
2.8
通讯作者：
Walker,Ve
中科院分区：
文献类型：
--
作者：
Meng,Quanxin;Olivero,OfeliaA;Fasco,MichaelJ;Bellisario,Ronald;Kaminsky,Laurence;Pass,KenA;Wade,NancyA;Abrams,ElaineJ;Nesel,CarolJ;Ness,RobertaB;Bigbee,WilliamL;O'Neill,JPatrick;Walker,DaleM;Poirier,MiriamC;Walker,Ve
对HIV-1感染母亲在产前接受AZT或AZT联合2‘，3’-二脱氧-3‘-硫代胞苷(3TC)治疗的未感染婴儿脐血中的3’-叠氮-3‘-双脱氧胸苷(AZT)代谢和AZT掺入核DNA的若干系统和细胞标志物进行了检测。此外，对这些婴儿的药理终点、AZT-DNA掺入水平和先前报道的突变反应之间的关系进行了评估。采用AZT和3TC特异性放射免疫分析(RIAs)或高效液相色谱与AZT-RIA联用的方法，以未感染HIV的母亲所生婴儿为对照，分别检测血浆中AZT和AZT-葡萄糖醛酸苷水平、脐血单个核细胞中AZT、AZT磷酸化的AZT细胞水平以及AZT或3TC的DNA掺入。AZT暴露组婴儿AZT-DNA掺入水平(71%；n=7)低于AZT-3TC组(100%；n=21)，AZT-DNA平均掺入水平(14.6±6.3AZT/106个核苷酸)显著低于AZT-3TC暴露组(51.6±10.2AZT/106个核苷酸；P=0.028)。在少数暴露于AZT-3TC的新生儿中，发现低水平的3TC-DNA掺入与同一样本中的AZT-DNA掺入值相关。在所研究的代谢物中，核苷类似物暴露婴儿的AZT-二磷酸和AZT-三磷酸水平以及AZT-三磷酸和AZT-DNA掺入量之间呈正相关。然而，在接受核苷类似物治疗的同一人群中，AZT-DNA掺入水平与报道的体细胞突变频率没有很好的相关性。虽然这些数据支持在妊娠期继续使用以AZT为基础的治疗，但接受产前AZT治疗的婴儿应该长期监测其对健康的不利影响。环境。摩尔。《诱变剂》，2007年。©2007 Wiley-Liss Inc.
Several systemic and cellular markers of 3′‐azido‐3′‐dideoxythymidine (AZT) metabolism and AZT incorporation into nuclear DNA were measured in cord blood from uninfected infants born to HIV‐1‐infected mothers receiving prepartum therapies based on AZT or AZT in combination with 2′,3′‐dideoxy‐3′‐thiacytidine (3TC). In addition, the relationships among these pharmacological end points, levels of AZT‐DNA incorporation, and the previously reported mutagenic responses in these infants were evaluated. AZT‐ and 3TC‐specific radioimmunoassays (RIAs), or HPLC coupled with AZT‐RIA, were used to measure plasma levels of AZT and the AZT‐glucuronide, and cellular levels of AZT, phosphorylated AZT, and DNA incorporation of AZT or 3TC in cord blood mononuclear cells from treated infants compared with unexposed controls born to HIV‐uninfected mothers. Fewer infants had detectable AZT‐DNA incorporation levels in the group exposed to AZT (71%;n= 7) compared with those receiving AZT‐3TC (100%;n= 21), and the mean AZT‐DNA incorporation for AZT‐exposed infants (14.6 ± 6.3 AZT/106nucleotides) was significantly lower than that in AZT‐3TC exposed infants (51.6 ± 10.2 AZT/106nucleotides;P= 0.028). Low levels of 3TC‐DNA incorporation found in a few AZT‐3TC‐exposed newborns correlated with AZT‐DNA incorporation values in the same samples. Among the metabolites studied, there were positive correlations between levels of AZT‐diphosphate and AZT‐triphosphate, and AZT‐triphosphate and AZT‐DNA incorporation, in nucleoside analog‐exposed infants. Levels of AZT‐DNA incorporation, however, did not correlate well with the reported frequencies of somatic mutations in the same population of nucleoside analog‐treated children. While these data support the continued use of AZT‐based therapies during pregnancy, infants receiving prepartum AZT should be monitored long‐term for adverse health effects. Environ. Mol. Mutagen., 2007. © 2007 Wiley‐Liss, Inc.