Critical role of free cytosolic calcium, but not uncoupling, in mitochondrial permeability transition and cell death induced by diclofenac oxidative metabolites in immortalized human hepatocytes

Lim, Miao Shan; Lim, Priscilla L.K.; Gupta, Rashi; Boelsterli, Urs A.

doi:10.1016/j.taap.2006.09.012

Cited by 65 publications

(44 citation statements)

References 33 publications

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“…Meanwhile, intestinal mucosal protection is weakened because of DCF's pharmacological inhibition of both COX-1 and COX-2 (Menasse et al, 1978), causing a decrease in protective prostaglandins. Simultaneously, the highly permeable DCF enters enterocytes and exerts further injury through mitochondrial dysfunction, leading to apoptosis (Gomez-Lechon et al, 2003;Lim et al, 2006). Unbound DCF-AG may also dissociate into DCF and glucuronic acid, intensifying diclofenac-induced mitochondrial dysfunction.…”

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confidence: 99%

Multidrug Resistance-Associated Protein 3 Plays an Important Role in Protection against Acute Toxicity of Diclofenac

et al. 2015

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Diclofenac (DCF) is a nonsteroidal anti-inflammatory drug commonly prescribed to reduce pain in acute and chronic inflammatory diseases. One of the main DCF metabolites is a reactive diclofenac acyl glucuronide (DCF-AG) that covalently binds to biologic targets and may contribute to adverse drug reactions arising from DCF use. Cellular efflux of DCF-AG is partially mediated by multidrug resistanceassociated proteins (Mrp). The importance of Mrp2 during DCFinduced toxicity has been established, yet the role of Mrp3 remains largely unexplored. In the present work, Mrp3-null (KO) mice were used to study the toxicokinetics and toxicodynamics of DCF and its metabolites. DCF-AG plasma concentrations were 90% lower in KO mice than in wild-type (WT) mice, indicating that Mrp3 mediates DCF-AG basolateral efflux. In contrast, there were no differences in DCF-AG biliary excretion between WT and KO, suggesting that only DCF-AG basolateral efflux is compromised by Mrp3 deletion. Susceptibility to toxicity was also evaluated after a single high DCF dose. No signs of injury were detected in livers and kidneys; however, ulcers were found in the small intestines. Furthermore, the observed intestinal injuries were consistently more severe in KO compared with WT. DCF covalent adducts were observed in liver and small intestines; however, staining intensity did not correlate with the severity of injuries, implying that tissues respond differently to covalent modification. Overall, the data provide strong evidence that (1) in vivo Mrp3 plays an important role in DCF-AG disposition and (2) compromised Mrp3 function can enhance injury in the gastrointestinal tract after DCF treatment.

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confidence: 99%

Multidrug Resistance-Associated Protein 3 Plays an Important Role in Protection against Acute Toxicity of Diclofenac

et al. 2015

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“…Furthermore, diclofenac is an environmental hazard to Gyps vultures due to its widespread use as a veterinary drug (37). In mammalian hepatocytes, diclofenac toxicity has been linked to mitochondrial dysfunction and oxidative metabolism by cytochrome P450s (15,30). Gene expression analysis has been performed on murine liver samples (7,9) and on human and rat hepatocytes (26) treated with diclofenac to further identify the underlying toxicity mechanisms.…”

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confidence: 99%

“…Furthermore, the pharmacological targets of diclofenac do not exist in yeast, thereby simplifying the test system, whereas many of the mechanisms underlying toxicity and resistance to chemicals and other environmental stresses are conserved (32). For example, both in yeast and in mammalian cells, diclofenac toxicity is related to mitochondrial dysfunction and elevated production of reactive oxygen species (ROS) (15,30,43). The availability of a well-annotated genome sequence makes yeast an ideal model system for genome-wide studies.…”

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confidence: 99%

Involvement of the Pleiotropic Drug Resistance Response, Protein Kinase C Signaling, and Altered Zinc Homeostasis in Resistance of Saccharomyces cerevisiae to Diclofenac

Leeuwen

Vermeulen

Vos

2011

Appl Environ Microbiol

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Diclofenac is a widely used analgesic drug that can cause serious adverse drug reactions. We used Saccharomyces cerevisiae as a model eukaryote with which to elucidate the molecular mechanisms of diclofenac toxicity and resistance. Although most yeast cells died during the initial diclofenac treatment, some survived and started growing again. Microarray analysis of the adapted cells identified three major processes involved in diclofenac detoxification and tolerance. In particular, pleiotropic drug resistance (PDR) genes and genes under the control of Rlm1p, a transcription factor in the protein kinase C (PKC) pathway, were upregulated in diclofenac-adapted cells. We tested if these processes or pathways were directly involved in diclofenac toxicity or resistance. Of the pleiotropic drug resistance gene products, the multidrug transporter Pdr5p was crucially important for diclofenac tolerance. Furthermore, deletion of components of the cell wall stress-responsive PKC pathway increased diclofenac toxicity, whereas incubation of cells with the cell wall stressor calcofluor white before the addition of diclofenac decreased its toxicity. Also, diclofenac induced flocculation, which might trigger the cell wall alterations. Genes involved in ribosome biogenesis and rRNA processing were downregulated, as were zinc-responsive genes. Paradoxically, deletion of the zinc-responsive transcription factor Zap1p or addition of the zinc chelator 1,10-phenanthroline significantly increased diclofenac toxicity, establishing a regulatory role for zinc in diclofenac resistance. In conclusion, we have identified three new pathways involved in diclofenac tolerance in yeast, namely, Pdr5p as the main contributor to the PDR response, cell wall signaling via the PKC pathway, and zinc homeostasis, regulated by Zap1p.

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“…The mechanism of opening of the MPT pore by diclofenac metabolites is not fully understood, though ROS and increase in cytosolic calcium have been suggested to be involved [88, 94, 95]. Oxidative intermediates of diclofenac were associated with increases in cytosolic calcium and the highly selective calcium chelator BAPTA greatly attenuated diclofenac-induced cell injury [88].…”

Section: Diclofenac Hepatotoxicitymentioning

confidence: 99%

“…On the other hand, it is possible that diclofenac metabolites may directly affect mitochondrial protein function by forming adducts to cause uncoupling of respiration, MPT pore opening and subsequent ATP depletion. In addition, oxidative metabolites may be involved in elevation of cytosolic calcium levels, which could also play a role in induction of the MPT and triggering of cell death [95]. Furthermore, opening of the MPT leads to the release of pro-apoptotic factors such as cytochrome c, which contributes to the activation of caspase-9 and -3, and leads to apoptotic cell death [97].…”

Section: Diclofenac Hepatotoxicitymentioning

confidence: 99%

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

et al. 2018

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Mitochondria are critical cellular organelles for energy generation and are now also recognized as playing important roles in cellular signaling. Their central role in energy metabolism, as well as their high abundance in hepatocytes, make them important targets for drug-induced hepatotoxicity. This review summarizes the current mechanistic understanding of the role of mitochondria in drug-induced hepatotoxicity caused by acetaminophen, diclofenac, anti-tuberculosis drugs such as rifampin and isoniazid, anti-epileptic drugs such as valproic acid and constituents of herbal supplements such as pyrrolizidine alkaloids. The utilization of circulating mitochondrial-specific biomarkers in understanding mechanisms of toxicity in humans will also be examined. In summary, it is well-established that mitochondria are central to acetaminophen-induced cell death. However, the most promising areas for clinically useful therapeutic interventions after acetaminophen toxicity may involve the promotion of adaptive responses and repair processes including mitophagy and mitochondrial biogenesis, In contrast, the limited understanding of the role of mitochondria in various aspects of hepatotoxicity by most other drugs and herbs requires more detailed mechanistic investigations in both animals and humans. Development of clinically relevant animal models and more translational studies using mechanistic biomarkers are critical for progress in this area.

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Critical role of free cytosolic calcium, but not uncoupling, in mitochondrial permeability transition and cell death induced by diclofenac oxidative metabolites in immortalized human hepatocytes

Cited by 65 publications

References 33 publications

Multidrug Resistance-Associated Protein 3 Plays an Important Role in Protection against Acute Toxicity of Diclofenac

Multidrug Resistance-Associated Protein 3 Plays an Important Role in Protection against Acute Toxicity of Diclofenac

Involvement of the Pleiotropic Drug Resistance Response, Protein Kinase C Signaling, and Altered Zinc Homeostasis in Resistance of Saccharomyces cerevisiae to Diclofenac

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

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