Abstract
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.
Highlights
Acetaminophen-induced toxicity, like many other drugs, may have a great deal of variations at the molecular, cellular, tissue, organ and organism levels [1,2]
We have previously shown that APAP induced cytotoxicity and cell death in macrophages is associated with increased oxidative stress, alterations in GSH pool, oxidative protein carbonylation and activation of mitochondrial apoptotic signals [24, 25]
Our results have demonstrated that the macrophages appear to be more sensitive to APAP toxicity compared to HepG2 cells at the same dose and time point
Summary
Acetaminophen-induced toxicity, like many other drugs, may have a great deal of variations at the molecular, cellular, tissue, organ and organism levels [1,2]. Metabolic alterations and increased oxidative stress is considered to be the key aspects of hepatotoxicity and apoptotic as well as necrotic cell death by acetaminophen (APAP) [3,4,5]. Reports suggest glutathione (GSH) depletion, oxidative stress and mitochondrial dysfunction in APAP-induced toxicity [3,10,11].The general consensus in APAP-induced toxicity is that the drug is mainly metabolized by various cytochrome P450s such as CYP2E1, CYP3A4, CYP1A2 and CYP1A1 to its active metabolite, mainly N-acetyl-p-benzoquinone imine (NAPQI) [12,13] which conjugates with GSH causing depletion of cellular GSH pools and increase in oxidative stress. The selective inhibition of proinflammatory signaling and induction of autophagy which removes damaged mitochondria, attenuates APAP-induced liver toxicity [7, 18, 20,21]
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