title: Nimesulide and 4'-Hydroxynimesulide as Bile Acid Transporters Inhibitors Are Contributory Factors for Drug-Induced Cholestasis.
abstract: Nimesulide (NIM) is a classic nonsteroidal anti-inflammatory drug. However, some patients treated with NIM experienced cholestatic liver injury. For this reason, we investigated the potential mechanism underlying NIM-induced cholestasis by using in vivo and in vitro models. Oral administration of 100 mg/kg/day NIM to Wistar rats for 5 days increased the levels of plasma total bile acids, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase by 1.49-, 1.31-, 1.60-, and 1.29-fold, respectively. In sandwich-cultured rat hepatocytes, NIM and 4'-hydroxynimesulide (M1) reduced the biliary excretion index of d8-taurocholic acid (d8-TCA) and 5 (and 6)-carboxy-2',7'-dichlorofluorescein in a concentration-dependent manner, indicating the inhibition of the efflux transporters bile salt export pump and multidrug resistance-associated protein 2, respectively. In suspended rat hepatocytes, NIM and M1 inhibited the uptake transporters of d8-TCA for Na+-taurocholate cotransporting polypeptide at IC50values of 21.3 and 25.0μM, respectively, and for organic anion-transporting proteins at IC50values of 45.6 and 39.4μM, respectively. By contrast, nitro-reduced NIM and the further acetylated metabolite did not inhibit or only marginally inhibited these transporters at the maximum soluble concentrations. Inhibitory effects of NIM and M1 on human bile acid transporters were also confirmed using sandwich-cultured human hepatocytes. These data suggest that the inhibition of bile acid transporters by NIM and M1 is one of the biologic mechanisms of NIM-induced cholestasis.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China (L.Z., X.P., J.J., D.Z., X.C.); and the University of Chinese Academy of Sciences, Beijing, People's Republic of China (L.Z., J.J., D.Z., X.C.).
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China (L.Z., X.P., J.J., D.Z., X.C.); and the University of Chinese Academy of Sciences, Beijing, People's Republic of China (L.Z., J.J., D.Z., X.C.).
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Pang
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China (L.Z., X.P., J.J., D.Z., X.C.); and the University of Chinese Academy of Sciences, Beijing, People's Republic of China (L.Z., J.J., D.Z., X.C.).
authors.forename: Jingfang
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China (L.Z., X.P., J.J., D.Z., X.C.); and the University of Chinese Academy of Sciences, Beijing, People's Republic of China (L.Z., J.J., D.Z., X.C.).
authors.forename: Dafang
authors.initials: D
authors.lastname: Zhong
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China (L.Z., X.P., J.J., D.Z., X.C.); and the University of Chinese Academy of Sciences, Beijing, People's Republic of China (L.Z., J.J., D.Z., X.C.) xychen@simm.ac.cn.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000633:toxicity*; D001647:Bile Acids and Salts / Q000097:blood / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D018929:Cell Culture Techniques; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism; D002779:Cholestasis / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008111:Liver Function Tests; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D017208:Rats, Wistar; D013449:Sulfonamides / Q000378:metabolism / Q000633:toxicity*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D013449:Sulfonamides; C037643:bile acid binding proteins; C055891:4-nitro-2-(4'-hydroxyphenoxy)methanesulfonanilide; C012655:nimesulide