Toxicological evaluation of acyl glucuronides utilizing half-lives, peptide adducts, and immunostimulation assays.
Toxicological evaluation of acyl glucuronides utilizing half-lives, peptide adducts, and immunostimulation assays.
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利用半衰期、肽加合物和免疫刺激测定对酰基葡萄糖苷酸进行毒理学评估。
DOI：
10.1016/j.tiv.2015.10.013
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Tsuyoshi Yokoi and Toshiyuki Kume.
中科院分区：
文献类型：
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作者：
Atsushi Iwamura;Masahito Ito;Hideaki Mitsui;Jun Hasegawa;Keigo Kosaka;Ichiro Kino;Minoru Tsuda;Miki Nakajima;Tsuyoshi Yokoi and Toshiyuki Kume.
葡萄糖醛酸化是内源性和外源性底物的重要II相代谢途径，通常被认为是一种解毒途径，但酰基葡萄糖醛酸苷（AGs）因其不稳定性而与内源性蛋白质共价结合，被认为与羧酸类药物的毒性有关。然而，这一理论仍然存在争议。本研究首先对21种药物的AGs进行了体外半衰期、肽加合物和免疫刺激试验，并分析了其与药物毒性类别的关系。在本研究中检测的所有停药药物的AG中观察到短半衰期、肽加合物和免疫刺激。免疫刺激试验比半衰期和肽加合物试验具有更高的灵敏度、特异性和准确性。其次，通过体内研究研究了佐美酸酰基葡糖苷酸（ZP-AG）对佐美酸（ZP）肾毒性的作用。用酯酶抑制剂和谷胱甘肽合成抑制剂预处理建立ZP肾损伤小鼠模型。结果表明，ZP-AG在肾脏中的蓄积是导致肾毒性的原因。这项研究为药物开发中AG毒性的评价提供了新的见解。
Glucuronidation is an important phase II metabolic pathway for endogenous and exogenous substrates and is generally considered as a detoxification pathway, but acyl glucuronides (AGs) have been believed to be related with the toxicity of carboxyl acid drugs, because AGs covalently bind to endogenous proteins owing to their instability. However, the theory remains controversial. In this study, first, in vitro assays of half-lives, peptide adducts and immunostimulation of AGs of 21 drugs were performed, and the relationship to toxic categories of drugs was analyzed. Short half-lives, peptide adducts and immunostimulation were observed in AGs of all withdrawn drugs tested in this study. The immunostimulation assay showed higher sensitivity, specificity, and accuracy than half-lives and peptide adducts assays. Second, responsibility of zomepirac acyl glucuronide (ZP-AG) for renal toxicity by zomepirac (ZP) was investigated by in vivo studies. ZP-induced kidney injury mouse model was established by pretreatment with an esterase inhibitor and a glutathione synthesis inhibitor. It was demonstrated that ZP-AG accumulation in kidney was responsible for the renal toxicity. This study provides new insight into the evaluation of AG toxicity in drug development.