Iwamura Atsushi, Watanabe Katsuhito, Akai Sho, Nishinosono Tsubasa, Tsuneyama Koichi, Oda Shingo, Kume Toshiyuki, Yokoi Tsuyoshi
Drug Metabolism and Pharmacokinetics Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (A.I., T.K.); Department of Drug Safety Sciences, Nagoya University Graduate School of Medicine, Aichi, Japan (K.W., S.A., T.N., S.O., T.Y.); Department of Molecular and Environmental Pathology, Institute of Health Biosciences, Tokushima University Graduate School, Tokushima, Japan (K.T.); and Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Ishikawa, Japan (A.I.)
Drug Metabolism and Pharmacokinetics Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (A.I., T.K.); Department of Drug Safety Sciences, Nagoya University Graduate School of Medicine, Aichi, Japan (K.W., S.A., T.N., S.O., T.Y.); Department of Molecular and Environmental Pathology, Institute of Health Biosciences, Tokushima University Graduate School, Tokushima, Japan (K.T.); and Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Ishikawa, Japan (A.I.).
Drug Metab Dispos. 2016 Jul;44(7):888-96. doi: 10.1124/dmd.116.069575. Epub 2016 Apr 25.
Glucuronidation, an important phase II metabolic route, is generally considered to be a detoxification pathway. However, acyl glucuronides (AGs) have been implicated in the toxicity of carboxylic acid drugs due to their electrophilic reactivity. Zomepirac (ZP) was withdrawn from the market because of adverse effects such as renal toxicity. Although ZP is mainly metabolized to acyl glucuronide (ZP-AG) by UDP-glucuronosyltransferase, the role of ZP-AG in renal toxicity is unknown. In this study, we established a ZP-induced kidney injury mouse model by pretreatment with tri-o-tolyl phosphate (TOTP), a nonselective esterase inhibitor, and l-buthionine-(S,R)-sulfoximine (BSO), a glutathione synthesis inhibitor. The role of ZP-AG in renal toxicity was investigated using this model. The model showed significant increases in blood urea nitrogen (BUN) and creatinine (CRE), but not alanine aminotransferase. The ZP-AG concentrations were elevated by cotreatment with TOTP in the plasma and liver and especially in the kidney. The ZP-AG concentrations in the kidney correlated with values for BUN and CRE. Upon histopathological examination, vacuoles and infiltration of mononuclear cells were observed in the model mouse. In addition to immune-related responses, oxidative stress markers, such as the glutathione/disulfide glutathione ratio and malondialdehyde levels, were different in the mouse model. The suppression of ZP-induced kidney injury by tempol, an antioxidant agent, suggested the involvement of oxidative stress in ZP-induced kidney injury. This is the first study to demonstrate that AG accumulation in the kidney by TOTP and BSO treatment could explain renal toxicity and to show the in vivo toxicological potential of AGs.
葡糖醛酸化是一条重要的Ⅱ相代谢途径，通常被认为是一种解毒途径。然而，由于其亲电反应性，酰基葡糖醛酸（AGs）与羧酸类药物的毒性有关。佐美酸（ZP）因肾毒性等不良反应而退市。虽然ZP主要通过尿苷二磷酸葡糖醛酸基转移酶代谢为酰基葡糖醛酸（ZP-AG），但ZP-AG在肾毒性中的作用尚不清楚。在本研究中，我们通过用非选择性酯酶抑制剂磷酸三邻甲苯酯（TOTP）和谷胱甘肽合成抑制剂L-丁硫氨酸-（S，R）-亚砜亚胺（BSO）进行预处理，建立了ZP诱导的肾损伤小鼠模型。使用该模型研究了ZP-AG在肾毒性中的作用。该模型显示血尿素氮（BUN）和肌酐（CRE）显著升高，但谷丙转氨酶未升高。与TOTP共同处理可使血浆、肝脏尤其是肾脏中的ZP-AG浓度升高。肾脏中的ZP-AG浓度与BUN和CRE值相关。组织病理学检查发现，模型小鼠出现空泡和单核细胞浸润。除了免疫相关反应外，模型小鼠的氧化应激标志物，如谷胱甘肽/二硫化谷胱甘肽比值和丙二醛水平也有所不同。抗氧化剂tempol对ZP诱导的肾损伤的抑制作用表明氧化应激参与了ZP诱导的肾损伤。这是第一项证明通过TOTP和BSO处理使AG在肾脏中蓄积可解释肾毒性，并显示AG体内毒理学潜力的研究。
