Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom.
Proc Natl Acad Sci U S A. 2013 Dec 3;110(49):19932-7. doi: 10.1073/pnas.1311535110. Epub 2013 Oct 28.
The Indian subcontinent is the only region where arsenic contamination of drinking water coexists with widespread resistance to antimonial drugs that are used to treat the parasitic disease visceral leishmaniasis. We have previously proposed that selection for parasite resistance within visceral leishmaniasis patients who have been exposed to trivalent arsenic results in cross-resistance to the related metalloid antimony, present in the pentavalent state as a complex in drugs such as sodium stibogluconate (Pentostam) and meglumine antimonate (Glucantime). To test this hypothesis, Leishmania donovani was serially passaged in mice exposed to arsenic in drinking water at environmentally relevant levels (10 or 100 ppm). Arsenic accumulation in organs and other tissues was proportional to the level of exposure and similar to that previously reported in human liver biopsies. After five monthly passages in mice exposed to arsenic, isolated parasites were found to be completely refractory to 500 μg · mL(-1) Pentostam compared with the control passage group (38.5 μg · mL(-1)) cultured in vitro in mouse peritoneal macrophages. Reassessment of resistant parasites following further passage for 4 mo in mice without arsenic exposure showed that resistance was stable. Treatment of infected mice with Pentostam confirmed that resistance observed in vitro also occurred in vivo. We conclude that arsenic contamination may have played a significant role in the development of Leishmania antimonial resistance in Bihar because inadequate treatment with antimonial drugs is not exclusive to India, whereas widespread antimonial resistance is.
印度次大陆是唯一一个饮用水砷污染与广泛抗锑药物耐药并存的地区，而这些抗锑药物被用于治疗寄生虫病内脏利什曼病。我们之前曾提出，在接触三价砷的内脏利什曼病患者中，寄生虫耐药性的选择导致对相关类金属锑的交叉耐药，而锑在五价状态下以复杂形式存在于药物中，如葡萄糖酸锑钠（Pentostam）和葡甲胺锑（Glucantime）。为了验证这一假设，我们在环境相关水平（10 或 100 ppm）的饮用水中暴露于砷的小鼠中对利什曼原虫（Leishmania donovani）进行了连续传代。器官和其他组织中的砷积累与暴露水平成正比，与之前在人类肝活检中报道的相似。在暴露于砷的小鼠中进行了五次每月传代后，与在体外培养于小鼠腹腔巨噬细胞中的对照传代组（38.5 μg·mL(-1))相比，分离的寄生虫对 500 μg·mL(-1) Pentostam 完全耐药。在没有砷暴露的小鼠中进一步传代 4 个月后重新评估耐药寄生虫，发现耐药性稳定。用 Pentostam 治疗感染小鼠证实了体外观察到的耐药性也发生在体内。我们得出结论，砷污染可能在比哈尔邦利什曼原虫抗锑耐药性的发展中发挥了重要作用，因为抗锑药物的治疗不足不仅在印度存在，而且广泛存在抗锑耐药性。
