Enhancement of zidovudine transfer to molt-4 cells, a human t-cell model, by dehydroepiandrosterone sulfate
Enhancement of zidovudine transfer to molt-4 cells, a human t-cell model, by dehydroepiandrosterone sulfate
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通过硫酸脱氢表雄酮增强齐多夫定向 molt-4 细胞（一种人类 T 细胞模型）的转移
DOI：
10.1002/jps.22624
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Nakashima E.
中科院分区：
文献类型：
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作者：
Nishimura T;Tanaka J;Tomi M;Seki Y;Kose N;Sai Y;Nakashima E.
改善核苷逆转录酶抑制剂抗逆转录病毒治疗的一种可能方法是增强抑制剂向CD 4阳性T细胞的递送。我们以前表明，脱氢表雄酮硫酸盐（DHEAS）增强齐多夫定（AZT）转移到合胞体滋养细胞。在这里，我们调查了DHEAS是否也能增强AZT转移到人T淋巴细胞的细胞模型中，以及AZT是否被特定的运输系统吸收。测定了DHEAS和相关化合物对Molt-4细胞（人CD 4阳性T细胞模型）摄取[3 H]AZT和其他核苷的影响。Molt-4细胞摄取[~ 3 H]AZT对硝基苄硫肌苷不敏感，呈pH依赖性，1 mm乙基异丙氨氯吡咪可显著抑制[~ 3 H]AZT摄取。在DHEAS存在下，Molt-4细胞的[3 H]AZT摄取增加，而其他核苷的摄取减少。动力学研究表明，DHEAS的存在下，最大摄取速度（30分钟）增加。使用DHEAS的结构类似物研究了AZT摄取增强活性的结构要求。雌酮-3-硫酸酯和16α-羟基DHEAS也能促进Molt-4细胞摄取AZT。使用摄取增强剂可能是提高抗逆转录病毒治疗疗效的一个好策略。© 2011 Wiley-Liss公司。和American Pharmacologist Association J Pharm Sci 100：3959-3967，2011
A possible approach to improve antiretroviral therapy with nucleoside reverse transcriptase inhibitors is to enhance inhibitor delivery to CD4-positive T cells. We previously showed that dehydroepiandrosterone sulfate (DHEAS) enhances zidovudine (AZT) transfer into syncytiotrophoblast. Here, we investigated whether DHEAS also enhances AZT transfer into a cellular model of human T lymphocytes, and whether AZT is taken up by a specific transport system. The effects of DHEAS and related compounds on the uptake of [3H]AZT and other nucleosides by Molt-4 cells (a model of human CD4-positive T cells) were measured. [3H]AZT uptake by Molt-4 cells was nitrobenzylthioinosine insensitive and pH dependent, and the uptake was significantly inhibited by 1 mm ethylisopropylamiloride. [3H]AZT uptake by Molt-4 cells was increased in the presence of DHEAS, whereas uptake of other nucleosides was reduced. Kinetic study revealed that the maximum uptake velocity (up to 30 min) was increased in the presence of DHEAS. The structural requirements for AZT uptake-enhancing activity were studied using structural analogues of DHEAS. Estrone-3-sulfate and 16α-hydroxy DHEAS also enhanced AZT uptake into Molt-4 cells. The use of uptake enhancers may be a good strategy to improve the efficacy of antiretroviral therapy. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3959–3967, 2011