Tatematsu Yohei, Hayashi Hiroki, Taguchi Ryo, Fujita Haruhi, Yamamoto Atsushi, Ohkura Kazuto
Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science.
Biol Pharm Bull. 2016;39(2):278-84. doi: 10.1248/bpb.b15-00717.
Hepatotoxicity is a known side effect of nonsteroidal anti-inflammatory drugs (NSAIDs). In the present study, the effects of N-phenylanthranilic acid (NPA) scaffold NSAIDs on rat liver mitochondria were examined. Mefenamic acid (MEF, 200 µM) induced mitochondrial swelling, which was inorganic phosphate (Pi)-dependent and suppressed by cyclosporin A (CsA, 2.5 µM), similar to calcium-induced swelling. Mitochondrial swelling was also observed following the addition of 200 µM flufenamic acid (FLU), meclofenamic acid (MCL), and tolfenamic acid (TOL). Less swelling was observed with the addition of 200 µM diclofenac (DIC) or NPA. Diphenylamine (DPA)-induced swelling occurred in a Pi-independent manner and was not sensitive to CsA. The mechanism by which DPA interacted with the mitochondrial inner membrane differed from those of the other NPA scaffold NSAIDs. The addition of 50 µM MEF, MCL, TOL, and FLU had uncoupling effects in mitochondrial inner membrane. These NSAIDs dose-dependently obstructed electron transport in the respiratory chain. NSAIDs are known to have various dynamic structures, and the solvation free energies (dGWs: an index of stereo-hydrophobicity) of the conformers obtained were determined using a molecular orbital analysis. The relationship between the dynamic structures and swelling induced by NPA scaffold NSAIDs was also examined.
肝毒性是非甾体抗炎药（NSAIDs）已知的副作用。在本研究中，研究了N-苯基邻氨基苯甲酸（NPA）骨架的非甾体抗炎药对大鼠肝线粒体的影响。甲芬那酸（MEF，200μM）诱导线粒体肿胀，这是无机磷酸盐（Pi）依赖性的，并被环孢素A（CsA，2.5μM）抑制，类似于钙诱导的肿胀。加入200μM氟芬那酸（FLU）、甲氯芬那酸（MCL）和托芬那酸（TOL）后也观察到线粒体肿胀。加入200μM双氯芬酸（DIC）或NPA时观察到的肿胀较少。二苯胺（DPA）诱导的肿胀以不依赖Pi的方式发生，且对CsA不敏感。DPA与线粒体内膜相互作用的机制与其他NPA骨架的非甾体抗炎药不同。加入50μM MEF、MCL、TOL和FLU对线粒体内膜有解偶联作用。这些非甾体抗炎药剂量依赖性地阻碍呼吸链中的电子传递。已知非甾体抗炎药具有各种动态结构，并使用分子轨道分析确定了所得构象体的溶剂化自由能（dGWs：立体疏水性指标）。还研究了NPA骨架非甾体抗炎药的动态结构与肿胀之间的关系。
