Masubuchi Y, Saito H, Horie T
Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan.
J Pharmacol Exp Ther. 1998 Oct;287(1):208-13.
Hepatotoxicity is one of the common side effects of nonsteroidal anti-inflammatory drugs (NSAIDs). We investigated the cytotoxicity of 18 acidic NSAIDs (3 salicylic acids, 3 anthranilic acids, 6 arylacetic acids, 6 arylpropionic acids) to freshly isolated rat hepatocytes as assessed by the NSAID-induced leakage of lactate dehydrogenase (LDH) in order to determine structural requirements for the direct hepatotoxicity of the NSAIDs. Diflunisal (salicylic acids), flufenamic acid, mefenamic acid, tolfenamic acid (anthranilic acids), diclofenac, indomethacin, acemetacin (arylacetic acids) and flurbiprofen (arylpropionic acids) caused significant LDH leakage, indicating that substituent position of a carboxyl group does not relate to the hepatotoxicity of the NSAIDs. Because the cytotoxic NSAIDs were of two types as classified by their "skeleton," diphenyl and diphenylamine, we tested the cytotoxicity of the compounds. Diphenyl did not cause LDH leakage, but diflunisal, which has the diphenyl structure, was cytotoxic. On the other hand, diphenylamine induced LDH leakage to the same degree as diclofenac, which has the diphenylamine structure. Therefore, diphenylamine itself was suggested to be responsible for the cytotoxicity of diclofenac and anthranilic acids, whereas a substituted group(s) in addition to diphenyl structure seems to be important for diflunisal cytotoxicity. All of the cytotoxic NSAIDs and diphenylamine extensively decreased hepatocellular ATP content, whereas the noncytotoxic NSAID did not, indicating that the NSAID-induced decrease in ATP, probably by their uncoupling effects on mitochondrial oxidative phosphorylation, is involved in the hepatotoxicity of the NSAIDs.
肝毒性是非甾体抗炎药（NSAIDs）常见的副作用之一。我们通过检测NSAIDs诱导的乳酸脱氢酶（LDH）泄漏情况，研究了18种酸性NSAIDs（3种水杨酸类、3种邻氨基苯甲酸类、6种芳基乙酸类、6种芳基丙酸类）对新鲜分离的大鼠肝细胞的细胞毒性，以确定NSAIDs直接肝毒性的结构要求。双氟尼酸（水杨酸类）、氟芬那酸、甲芬那酸、托芬那酸（邻氨基苯甲酸类）、双氯芬酸、吲哚美辛、阿西美辛（芳基乙酸类）和氟比洛芬（芳基丙酸类）均导致显著的LDH泄漏，这表明羧基的取代位置与NSAIDs的肝毒性无关。由于具有细胞毒性的NSAIDs按其“骨架”可分为两类，即二苯基和二苯胺基，我们对这些化合物的细胞毒性进行了测试。二苯基未引起LDH泄漏，但具有二苯基结构的双氟尼酸具有细胞毒性。另一方面，二苯胺诱导的LDH泄漏程度与具有二苯胺结构的双氯芬酸相同。因此，提示二苯胺本身是双氯芬酸和邻氨基苯甲酸类化合物细胞毒性的原因，而除二苯基结构外的取代基团似乎对双氟尼酸的细胞毒性很重要。所有具有细胞毒性的NSAIDs和二苯胺均能显著降低肝细胞ATP含量，而非细胞毒性的NSAIDs则不会，这表明NSAIDs诱导的ATP减少，可能是由于它们对线粒体氧化磷酸化的解偶联作用，与NSAIDs的肝毒性有关。
