Remirez D, Commandeur J N, Groot E, Vermeulen N P
Leiden, Amsterdam Center for Drug Research (LACDR), Department of Pharmacochemistry, Vriji Universiteit, Amsterdam, Netherlands.
Eur J Pharmacol. 1995 Dec 7;293(4):301-8. doi: 10.1016/0926-6917(95)90049-7.
The protective effects of lobenzarit, an antioxidative agent and antirheumatic drug, on the cytotoxicity of paracetamol in rat hepatocytes were studied, as well as the inhibitory effects of lobenzarit on cytochrome P-450s and glutathione S-transferases (GSTs) in rat liver. Paracetamol was selected as a model toxin, since it is known to be bioactivated by specific cytochrome P-450s presumably to N-acetyl-p-benzoquinoneimine, a reactive metabolite which upon overdosage of paracetamol causes protein and non-protein thiol depletion, lipid peroxidation and cytotoxicity measurable as LDH leakage. At concentrations of lobenzarit of 0.2 and 0.3 mM, added 30 min before paracetamol, the drug prevented paracetamol-induced leakage of lactate dehydrogenase (LDH) almost completely and lipid peroxidation (LPO) and depletion of glutathione (GSH) substantially and also the formation of the 3-glutathionyl conjugate of paracetamol. However, at a concentration of 0.05 mM Lobenzarit did not protect anymore against the paracetamol toxicity, When added to the hepatocytes 1 h and 2 h before paracetamol, 0.05 and 0.2 and 0.3 mM concentrations of lobenzarit did not protect against the cytotoxicity induced by paracetamol either. Lobenzarit did not inhibit cytochromes P-450 1A1/1A2, 2B1/2B2 and 2E1 which were measured as ethoxyresorufin O-deethylation (EROD) activity in beta-naphthoflavone-induced rat liver microsomes, as pentoxyresorufin de-pentylation (PROD) activity in phenobarbital-induced microsomes and as p-nitrophenol hydroxylation (PNPH) activity in pyrazol-induced microsomes. Lobenzarit did not show inhibition of glutathione S-transferase (GST) activity towards 1-chloro-2,4-dinitrobenzene (CDNB) in cytosol from liver of rats treated with phenobarbital, pyrazol and beta-naphthoflavone either. It is concluded that the cytoprotective effect of lobenzarit is most likely due to its antioxidant effects and/or to its ability to stimulate GSH reductase.
研究了抗氧化剂和抗风湿药物氯苯扎利对大鼠肝细胞中对乙酰氨基酚细胞毒性的保护作用，以及氯苯扎利对大鼠肝脏中细胞色素P - 450和谷胱甘肽S - 转移酶（GSTs）的抑制作用。选择对乙酰氨基酚作为模型毒素，因为已知它可被特定的细胞色素P - 450生物活化，大概生成N - 乙酰 - 对 - 苯醌亚胺，一种活性代谢产物，对乙酰氨基酚过量时会导致蛋白质和非蛋白质硫醇耗竭、脂质过氧化以及可通过乳酸脱氢酶（LDH）泄漏来衡量的细胞毒性。在对乙酰氨基酚之前30分钟加入浓度为0.2和0.3 mM的氯苯扎利，该药物几乎完全阻止了对乙酰氨基酚诱导的乳酸脱氢酶（LDH）泄漏，显著减轻了脂质过氧化（LPO）和谷胱甘肽（GSH）耗竭，还阻止了对乙酰氨基酚的3 - 谷胱甘肽共轭物的形成。然而，浓度为0.05 mM的氯苯扎利不再对乙酰氨基酚毒性起保护作用。当在对乙酰氨基酚之前1小时和2小时加入到肝细胞中时，0.05、0.2和0.3 mM浓度的氯苯扎利也不能保护细胞免受对乙酰氨基酚诱导的细胞毒性。氯苯扎利没有抑制在β - 萘黄酮诱导的大鼠肝微粒体中以乙氧基试卤灵O - 脱乙基化（EROD）活性测定的细胞色素P - 450 1A1/1A2、2B1/2B2和2E1，在苯巴比妥诱导的微粒体中以戊氧基试卤灵脱戊基化（PROD）活性测定的这些酶，以及在吡唑诱导的微粒体中以对硝基苯酚羟基化（PNPH）活性测定的这些酶。氯苯扎利对用苯巴比妥、吡唑和β - 萘黄酮处理的大鼠肝脏胞质溶胶中谷胱甘肽S - 转移酶（GST）对1 - 氯 - 2,4 - 二硝基苯（CDNB）的活性也没有抑制作用。得出的结论是，氯苯扎利的细胞保护作用很可能归因于其抗氧化作用和/或刺激谷胱甘肽还原酶的能力。
