Raza Haider, John Annie
Department of Biochemistry, College of Medicine and Health Sciences, UAE University, PO Box 17666, Al Ain, United Arab Emirates.
PLoS One. 2015 Dec 29;10(12):e0145965. doi: 10.1371/journal.pone.0145965. eCollection 2015.
Non-steroidal anti-inflammatory drugs (NSAIDs), including acetaminophen (APAP), have been reported to induce cytotoxicity in cancer and non-cancerous cells. Overdose of acetaminophen (APAP) causes liver injury in humans and animals. Hepatic glutathione (GSH) depletion followed by oxidative stress and mitochondrial dysfunction are believed to be the main causes of APAP toxicity. The precise molecular mechanism of APAP toxicity in different cellular systems is, however, not clearly understood. Our previous studies on mouse macrophage J774.2 cells treated with APAP strongly suggest induction of apoptosis associated with mitochondrial dysfunction and oxidative stress. In the present study, using human hepatoma HepG2 cells, we have further demonstrated that macrophages are a more sensitive target for APAP-induced toxicity than HepG2 cells. Using similar dose- and time-point studies, a marked increase in apoptosis and DNA fragmentation were seen in macrophages compared to HepG2 cells. Differential effects of APAP on mitochondrial respiratory functions and oxidative stress were observed in the two cell lines which are presumably dependent on the varying degree of drug metabolism by the different cytochrome P450s and detoxification by glutathione S-transferase enzyme systems. Our results demonstrate a marked increase in the activity and expression of glutathione transferase (GST) and multidrug resistance (MDR1) proteins in APAP-treated HepG2 cells compared to macrophages. This may explain the apparent resistance of HepG2 cells to APAP toxicity. However, treatment of these cells with diallyl sulfide (DAS, 200 μM), a known chemopreventive agent from garlic extract, 24 h prior to APAP (10 μmol/ml for 18h) exhibited comparable cytoprotective effects in the two cell lines. These results may help in better understanding the mechanism of cytotoxicity caused by APAP and cytoprotection by chemopreventive agents in cancer and non-cancerous cellular systems.
据报道，包括对乙酰氨基酚（APAP）在内的非甾体抗炎药（NSAIDs）可在癌细胞和非癌细胞中诱导细胞毒性。对乙酰氨基酚（APAP）过量会导致人和动物肝损伤。肝谷胱甘肽（GSH）耗竭，随后发生氧化应激和线粒体功能障碍，被认为是APAP毒性的主要原因。然而，APAP在不同细胞系统中毒性的确切分子机制尚不清楚。我们之前对用APAP处理的小鼠巨噬细胞J774.2细胞的研究强烈表明，细胞凋亡与线粒体功能障碍和氧化应激有关。在本研究中，我们使用人肝癌HepG2细胞进一步证明，与HepG2细胞相比，巨噬细胞是APAP诱导毒性更敏感的靶标。通过类似的剂量和时间点研究发现，与HepG2细胞相比，巨噬细胞中的细胞凋亡和DNA片段化显著增加。在这两种细胞系中观察到APAP对线粒体呼吸功能和氧化应激的不同影响，这可能取决于不同细胞色素P450的药物代谢程度和谷胱甘肽S-转移酶酶系统的解毒作用。我们的结果表明，与巨噬细胞相比，APAP处理的HepG2细胞中谷胱甘肽转移酶（GST）和多药耐药（MDR1）蛋白的活性和表达显著增加。这可能解释了HepG2细胞对APAP毒性的明显抗性。然而，在APAP（10 μmol/ml，处理18小时）处理前24小时，用二烯丙基硫醚（DAS，200 μM，一种来自大蒜提取物的已知化学预防剂）处理这些细胞，在两种细胞系中表现出相当的细胞保护作用。这些结果可能有助于更好地理解APAP引起的细胞毒性机制以及化学预防剂在癌症和非癌症细胞系统中的细胞保护作用。
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