2'-Deoxythymidine adducts from the anti-HIV drug nevirapine.
2'-Deoxythymidine adducts from the anti-HIV drug nevirapine.
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来自抗HIV药物奈韦拉平的2'-脱氧胸苷加合物。
DOI：
10.3390/molecules18054955
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发表时间：
2013-04-26
期刊：
影响因子：
--
通讯作者：
Marques MM
中科院分区：
文献类型：
--
作者：
Antunes AM;Wolf B;Oliveira MC;Beland FA;Marques MM
奈韦拉平（NVP）是一种非核苷类逆转录酶抑制剂（NNRTI），用于抗HIV-1。目前，NVP是发展中国家使用最广泛的抗艾滋病毒药物，用于联合治疗和预防母婴传播艾滋病毒。尽管NVP对HIV有效，但它会产生各种毒性反应，包括肝毒性和皮疹。它还与啮齿类动物肝肿瘤发生率增加有关。此外，流行病学数据表明，NNRTI的使用是艾滋病毒阳性患者非艾滋病定义癌症的一个风险因素。目前的证据支持NVP毒性中反应性亲电体的代谢活化的参与。NVP代谢包括氧化为12-羟基-NVP;随后的II相磺化产生亲电代谢产物12-磺酰基-NVP，能够与DNA反应产生共价加合物。由于2 '-脱氧胸苷（dT）加合物从几个烷化剂被认为是具有显着的致突变/致癌潜力，我们研究了NVP-dT加合物的形成在仿生条件下。为了实现这一目标，我们最初使用钯介导的Buchwald-Hartwig偶联策略制备和表征合成NVP-dT加合物标准品。合成标准品能够通过LC-ESI-MS鉴别鲑鱼睾丸DNA酶水解产物中的12-（2 '-脱氧胸苷-N3-基）-奈韦拉平（N3-NVP-dT），该酶水解产物与12-甲磺酰-NVP（12-磺酰-NVP的合成替代物）反应。N3-NVP-dT是一种潜在的细胞毒性和致突变性DNA损伤，也是dT与12-mesoxy-NVP反应后检测到的唯一dT特异性加合物。我们的数据表明，N3-NVP-dT可能在体内形成，并在NVP的肝毒性和/或推定的肝癌性中发挥作用。
Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used against HIV-1. Currently, NVP is the most widely used anti-HIV drug in developing countries, both in combination therapy and to prevent mother-to-child transmission of HIV. Despite its efficacy against HIV, NVP produces a variety of toxic responses, including hepatotoxicity and skin rash. It is also associated with increased incidences of hepatoneoplasias in rodents. In addition, epidemiological data suggest that NNRTI use is a risk factor for non-AIDS-defining cancers in HIV-positive patients. Current evidence supports the involvement of metabolic activation to reactive electrophiles in NVP toxicity. NVP metabolism includes oxidation to 12-hydroxy-NVP; subsequent Phase II sulfonation produces an electrophilic metabolite, 12-sulfoxy-NVP, capable of reacting with DNA to yield covalent adducts. Since 2’-deoxythymidine (dT) adducts from several alkylating agents are regarded as having significant mutagenic/carcinogenic potential, we investigated the formation of NVP-dT adducts under biomimetic conditions. Toward this goal, we initially prepared and characterized synthetic NVP-dT adduct standards using a palladium-mediated Buchwald-Hartwig coupling strategy. The synthetic standards enabled the identification, by LC-ESI-MS, of 12-(2'-deoxythymidin-N3-yl)-nevirapine (N3-NVP-dT) in the enzymatic hydrolysate of salmon testis DNA reacted with 12-mesyloxy-NVP, a synthetic surrogate for 12-sulfoxy-NVP. N3-NVP-dT, a potentially cytotoxic and mutagenic DNA lesion, was also the only dT-specific adduct detected upon reaction of dT with 12-mesyloxy-NVP. Our data suggest that N3-NVP-dT may be formed in vivo and play a role in the hepatotoxicity and/or putative hepatocarcinogenicity of NVP.
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影响因子：
4.1
作者：
Antunes AM;Godinho AL;Martins IL;Oliveira MC;Gomes RA;Coelho AV;Beland FA;Marques MM
通讯作者：
Marques MM
影响因子：
168.9
作者：
Jackson, JB;Musoke, P;Mmiro, F
通讯作者：
Mmiro, F
影响因子：
158.5
作者：
Lallemant, M;Jourdain, G;Thaineua, V
通讯作者：
Thaineua, V
影响因子：
3.6
作者：
CHANG, CJ;GOMES, JD;BYRN, SR
通讯作者：
BYRN, SR
影响因子：
168.9
作者：
Marseille, E;Kahn, JG;Jackson, JB
通讯作者：
Jackson, JB