Differential toxic effects of azathioprine, 6-mercaptopurine and 6-thioguanine on human hepatocytes
Differential toxic effects of azathioprine, 6-mercaptopurine and 6-thioguanine on human hepatocytes
复制标题
DOI：
10.1016/j.tiv.2007.12.004
复制
发表时间：
2008-04-01
影响因子：
3.2
通讯作者：
Morel, Fabrice
中科院分区：
文献类型：
--
作者：
Petit, Elise;Langouet, Sophie;Morel, Fabrice
硫嘌呤（硫嘌呤、6-巯基嘌呤和6-硫鸟嘌呤）是临床广泛使用的治疗性化合物，具有多种用途（自身免疫性疾病、移植后免疫抑制和癌症）。尽管有这些优点，但它们的治疗潜力受到偶尔的不良反应（骨髓毒性和肝毒性）和相对频繁的缺乏疗效的限制。先前的研究表明，硫唑嘌呤降低了大鼠肝细胞的活力。为了研究硫嘌呤对人肝脏的细胞毒性作用，我们使用了原代人肝细胞和高度分化的人肝癌细胞系HepaRG，分别用硫嘌呤、6-巯基嘌呤和6-硫嘌呤处理或不处理。同时，通过定量PCR检测参与硫嘌呤代谢、谷胱甘肽合成和抗氧化防御的基因表达。我们清楚地证明，人肝实质细胞比大鼠肝细胞对硫嘌呤治疗的敏感性低得多。处理96 h后出现毒性作用，与硫唑嘌呤和6-巯基嘌呤孵育24 h后观察到ATP耗竭。与6-硫鸟嘌呤相比，硫嘌呤和6-巯基嘌呤的毒性作用更为明显，这可能解释了只有这两种药物才能合成谷胱甘肽和诱导抗氧化酶。最后，我们还首次证明了硫唑嘌呤和6-巯基嘌呤对肌苷单磷酸脱氢酶的上调，这可能对鸟嘌呤核苷酸的从头生物合成和硫嘌呤代谢产生影响。(C) 2007 Elsevier Ltd.版权所有。
Thiopurines (azathioprine, 6-mercaptopurine and 6-thioguanine) are therapeutic compounds widely administered in the clinic for their multiple uses (autoirnmune diseases, post-transplant immunosuppression and cancer). Despite these advantages, their therapeutic potential is limited by occasional adverse effects (myelotoxicity and hepatotoxicity) and by a relatively frequent lack of efficacy. Previous studies have demonstrated that azathioprine decreased the viability of rat hepatocytes. In order to investigate cytotoxic effects of thiopurines in human liver, we used primary human hepatocytes and a highly differentiated human hepatoma cell line, HepaRG, treated or not with azathioprine, 6-mercaptopurine and 6-thioguanine. In parallel, expression of the genes involved in the metabolism of thiopurines, glutathione synthesis and antioxidant defences was measured by quantitative PCR. We clearly demonstrate that human liver parenchymal cells were much less sensitive than rat hepatocytes to thiopurine treatments. The toxic effects appeared after 96 h of treatment while ATP depletion was observed after a 24 h incubation with azathioprine and 6-mercaptopurine. Toxic effects were more pronounced for azathioprine and 6-mercaptopurine, when compared to 6-thioguanine, and might explain glutathione synthesis and antioxidant enzyme induction only by these two drugs. Finally, we also demonstrate for the first time an up-regulation by azathioprine and 6-mercaptopurine of inosine monophosphate dehydrogenase which might have consequences on the de novo biosynthesis of guanine nucleotides and thiopurines metabolism. (C) 2007 Elsevier Ltd. All rights reserved.