Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan.
Chem Biol Interact. 2010 Feb 12;183(3):363-8. doi: 10.1016/j.cbi.2009.11.024. Epub 2009 Dec 3.
Salicylic acid is a widely used nonsteroidal anti-inflammatory drug (NSAID). But it is known to cause serious liver damage occasionally. Mitochondrial dysfunction and oxidative stress are predicted to be the major factors of salicylic acid-induced liver injury. We investigated the influence of salicylic acid on ATP contents, oxygen consumption and lipid peroxidation in the presence of the same concentration of salicylic acid. Leakage of lactate dehydrogenase (LDH) was significantly higher in the presence of 5mM salicylic acid than in its absence. Salicylic acid-induced thiobarbituric acid-reactive substance (TBARS) formation and spontaneous chemiluminescence (CL) in rat hepatocytes, whereas antioxidants, such as promethazine (PMZ) and N,N-diphenylphenylenediamine (DPPD), suppressed both TBARS formation and LDH leakage. TBARS formation in rat liver microsomes was suppressed by diethyldithiocarbamate (a specific inhibitor of cytochrome P450 (CYP)2E1) and diclofenac (a specific inhibitor of CYP2C11). These results suggest that salicylic acid-induced lipid peroxidation was related to oxidative metabolism mediated by CYP2E1 and CYP2C11. On the other hand, 5mM salicylic acid induced a drastic decrease of ATP contents in rat isolated hepatocytes. Furthermore, mitochondrial respiration control ratio (RC ratio), calculated by State 3/State 4 also decreased with the increase of salicylic acid concentration. These findings suggest that salicylic acid would trigger mitochondrial dysfunction and cause ATP decrease, leading to lethal liver cell injury by lipid peroxidation, although this hypothesis remains to be elucidated in vivo.
水杨酸是一种广泛使用的非甾体抗炎药（NSAID）。但它偶尔会导致严重的肝损伤。线粒体功能障碍和氧化应激被预测为水杨酸引起肝损伤的主要因素。我们研究了在相同浓度的水杨酸存在下，水杨酸对 ATP 含量、耗氧量和脂质过氧化的影响。在存在 5mM 水杨酸的情况下，乳酸脱氢酶（LDH）的漏出明显高于不存在水杨酸的情况。水杨酸诱导的丙二醛（TBARS）形成和大鼠肝细胞的自发化学发光（CL），而抗氧化剂，如普罗米嗪（PMZ）和 N，N-二苯基对苯二胺（DPPD），抑制了 TBARS 形成和 LDH 漏出。二乙二硫代氨基甲酸盐（细胞色素 P450（CYP）2E1 的特异性抑制剂）和双氯芬酸（CYP2C11 的特异性抑制剂）抑制了大鼠肝微粒体中的 TBARS 形成。这些结果表明，水杨酸诱导的脂质过氧化与 CYP2E1 和 CYP2C11 介导的氧化代谢有关。另一方面，5mM 水杨酸诱导大鼠分离肝细胞中 ATP 含量急剧下降。此外，线粒体呼吸控制比（RC 比），通过 State 3/State 4 计算也随着水杨酸浓度的增加而降低。这些发现表明，水杨酸会引发线粒体功能障碍并导致 ATP 减少，从而通过脂质过氧化导致致命的肝细胞损伤，尽管这一假设在体内仍有待阐明。
