RT Journal Article
SR Electronic
T1 Zomepirac Acyl Glucuronide Is Responsible for Zomepirac-induced Acute Kidney Injury in Mice
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.116.069575
DO 10.1124/dmd.116.069575
A1 Atsushi Iwamura
A1 Katsuhito Watanabe
A1 Sho Akai
A1 Tsubasa Nishinosono
A1 Koichi Tsuneyama
A1 Shingo Oda
A1 Toshiyuki Kume
A1 Tsuyoshi Yokoi
YR 2016
UL http://dmd.aspetjournals.org/content/early/2016/04/25/dmd.116.069575.abstract
AB 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 Zomepirac (ZP) was withdrawn from the market because of adverse effects such as renal toxicity.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 non-selective 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 co-treatment 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.