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Chemical and Enzymatic Transformations of Nimesulide to GSH Conjugates through Reductive and Oxidative Mechanisms


, : Chemical and Enzymatic Transformations of Nimesulide to GSH Conjugates through Reductive and Oxidative Mechanisms. Chemical Research in Toxicology 28(12): 2267-2277

Nimesulide (NIM) is a nonsteroidal anti-inflammatory drug, and clinical treatment with NIM has been associated with severe hepatotoxicity. The bioactivation of nitro-reduced NIM (NIM-NH2), a major NIM metabolite, has been thought to be responsible for the hepatotoxicity of NIM. However, we found that NIM-NH2 did not induce toxic effects in primary rat hepatocytes. This study aimed to investigate other bioactivation pathways of NIM and evaluate their association with hepatotoxicity. After incubating NIM with NADPH- and GSH-supplemented human or rat liver microsomes, we identified two types of GSH conjugates: one was derived from the attachment of GSH to NIM-NH2 (NIM-NH2-GSH) and the other one was derived from a quinone-imine intermediate (NIM-OH-GSH). NIM-NH2-GSH was generated not only by the oxidative activation of NIM-NH2 but also from the reductive activation of NIM. Both NADPH and GSH could act as reducing agents. Moreover, aldehyde oxidase also participated in the reductive activation of NIM. NIM-OH-GSH was generated mainly from NIM via epoxidation with CYP1A2 as the main catalyzing enzyme. NIM was toxic to both primary human and rat hepatocytes, with IC50 values of 213 and 40 μM, respectively. Inhibition of the oxidative and reductive activation of NIM by the nonspecific CYP inhibitor 1-aminobenzotriazole and selective aldehyde oxidase inhibitor estradiol did not protect the cells from NIM-mediated toxicity. Moreover, pretreating cells with l-buthionine-sulfoximine (a GSH depletor) did not affect the cytotoxicity of NIM. These results suggested that oxidative and reductive activation of NIM did not cause the hepatotoxicity and that the parent drug concentration was associated with the cytotoxicity.

US$19.90

PMID: 26524229

DOI: 10.1021/acs.chemrestox.5b00290


Other references

Formiga, F.; Moga, I.; Pac, M.; Mitjavila, F.; Rivera, A.; Pujol, R., 1999: Mild presentation of systemic lupus erythematosus in elderly patients assessed by SLEDAI. Objective: Systemic lupus erythematosus (SLE) predominantly affects young patients. SLE starting in later life has a clinical presentation different than in younger patients. We have used the SLE Disease Activity Index (SLEDAI) to explore the rela...

Okulov Y.N., 1980: Types of vein quartz formations in the Turkestan Range. Zapiski Uzbekistanskogo Otdeleniya Vsesoyuznogo Mineralogicheskogo Obshchestva 33: 181-183

Andrén, L.; Svensson, A.; Dahlöf, B.; Eggertsen, R.; Hansson, L., 1983: Ketanserin in hypertension. Early clinical evaluation and dose finding study of a new 5-HT2 receptor antagonist. Ketanserin, a new 5-hydroxy-tryptamine antagonist, was given at three different dosage levels (double-blind, randomized) in a dose finding study for 2 months to 31 patients with mild to moderately severe essential hypertension. Treatment with keta...

Berridge, D.C.; Lees, T.A.; Chamberlain, J.; Jones, N.A., 1993: Eye protection for the vascular surgeon. Contamination occurring during vascular surgery was studied prospectively using a surgical mask incorporating a Splashguard visor. Over a 16-week period 78 vascular procedures were included; 44 were of < 2 h duration and 34 were of > or = 2...

Bayer, L.; Kaplay, I., 1975: A Bakony foldtani-oslenytani bibliografiaja. Bakony termeszettud Kut Eredmenyei, 9: 1-135

Parkhill, M.A.; Pronk, T.; Boldon, R.; Desrosiers, M.; Arnott, P.; Campbell, H.; Cyr, L.-Philippe; McCoy, S., 2008: The Maritime Soil Project; a New Brunswick perspective. Atlantic Geology 44: 32

Yao, T.Z. et al., 1989: Study on the harvest index of soybean in high-yield breeding. Harvest index, studied in 316 soyabean varieties, was negatively correlated with growth period, height, number of nodes on the main stem and mature plant weight. The harvest index of indeterminate, semideterminate, purple-flowered and pointed-leaf...

Grigaliunas, A.P., 1980: Regional external respiratory functions in infiltrative pulmonary tuberculosis under comprehensive therapy. Problemy Tuberkuleza: 44-47

Liebermann, H.T.; Meissner, J.; Schulze, P.; Thalmann, G., 1976: Various physical and chemical properties of the 73s unit of the foot-and-mouth disease virus. At all 3 studied FMD-viruses typs O2, A5 and C we could show the 73S unit in the analytical ultracentrifuge and in the electron microscope. 73S unit is found in the normal cycle of purification of virus and by density gradient centrifugation separ...

Macausland, W.R., 1952: Nylon replacement in arthritis of the hip. Revista Da Associacao Paulista de Cirurgioes Dentistas 18(1): 19-48