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Title: Mitochondrial permeability transition as a source of superoxide anion induced by the nitroaromatic drug nimesulide in vitro
Authors: Tay, V.K.S.
Wang, A.S.
Leow, K.Y.
Ong, M.M.K.
Boelsterli, U.A. 
Wong, K.P.
Keywords: Free radicals
Membrane permeability transition
Nitroaromatic drug
Superoxide anion
Issue Date: 2005
Source: Tay, V.K.S., Wang, A.S., Leow, K.Y., Ong, M.M.K., Boelsterli, U.A., Wong, K.P. (2005). Mitochondrial permeability transition as a source of superoxide anion induced by the nitroaromatic drug nimesulide in vitro. Free Radical Biology and Medicine 39 (7) : 949-959. ScholarBank@NUS Repository.
Abstract: Nimesulide, a widely used nonsteroidal anti-inflammatory drag containing a nitroaromatic moiety, has been associated with rare but serious hepatic adverse effects. The mechanisms underlying this idiosyncratic hepatotoxicity are unknown; however, both mitochondrial injury and oxidative stress have been implicated in contributing to liver injury in susceptible patients. The aim of this study was, first, to explore whether membrane permeability transition (MPT) could contribute to nimesulide's mitochondrial toxicity and, second, whether metabolism-derived reactive oxygen species (ROS) were responsible for MPT. We found that isolated mouse liver mitochondria readily underwent Ca 2+-dependent, cyclosporin A-sensitive MPT upon exposure to nimesulide (at ≥ 3 μM). Net increases in mitochondrial superoxide anion levels, determined with the fluorescent probe dihydroethidium, were induced by nimesulide only in the presence of Ca2+ and were cyclosporin A-sensitive, indicating that superoxide production was a consequence, rather than the cause, of MPT. In addition, nimesulide caused a rapid dissipation of the inner mitochondrial transmembrane potential (at ≥ 3 μM), followed by a concentration-dependent decrease in ATP biosynthesis. Because nimesulide, unlike the related nitroaromatic drag nilutamide, did not produce any detectable ROS during incubation with mouse hepatic microsomes, we conclude that mitochondrial uncoupling causes MPT and that ROS production is a secondary effect. © 2005 Elsevier Inc. All rights reserved.
Source Title: Free Radical Biology and Medicine
ISSN: 08915849
DOI: 10.1016/j.freeradbiomed.2005.05.013
Appears in Collections:Staff Publications

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