Diclofenac induces apoptosis in hepatocytes by alteration of mitochondrial function and generation of ROS

Gómez‐Lechón, M. José; Ponsoda, Xavier; O’Connor, Enrique; Donato, M. Teresa; Castell, José V.; Jover, Ramiro

doi:10.1016/j.bcp.2003.08.003

Cited by 161 publications

(102 citation statements)

References 52 publications

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“…Cell survival was evaluated as a percentage of viable cells in treated versus untreated control wells on the same plate (% cell viability). The amount of reactive oxygen species (ROS) present was determined in a similar manner, except cultures were incubated with DCFH-DA dye for 30 min, and readings were taken at 504 nm (Gomez-Lechon et al, 2003;Somogyi et al, 2007).…”

Section: In Vitro Toxicity Assaymentioning

confidence: 99%

The Pied Crow (Corvus Albus) Is Insensitive to Diclofenac at Concentrations Present in Carrion

Naidoo

Mompati

Duncan

et al. 2011

Journal of Wildlife Diseases

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ABSTRACT:Diclofenac, a nonsteroidal anti-inflammatory drug (NSAID), kills vultures (Gyps spp.) that consume tainted carcasses. As a result, vulture populations in India, Nepal, and Pakistan have been devastated. Studies on meloxicam and ketoprofen demonstrated that the toxicity of the NSAIDs is unpredictable, thereby necessitating individual testing of all available NSAIDs. Because it is no longer practical to use vultures for toxicity testing, we evaluated the Pied Crow (Corvus albus) as a model. Pied Crows (n56) were exposed to a dose of 0.8 and 10 mg/kg of diclofenac, with no signs of toxicity, and a rapid half-life of elimination. Using primary renal cell and hepatocyte cultures, a high tolerance was demonstrated at the cellular level. Meta-analysis of pharmacokinetic data for the Domestic Chicken (Gallus gallus) and the African White-backed (Gyps africanus), Cape Griffon (Gyps coprotheres), and Turkey Vultures (Cathartes aura) showed a trend toward toxicity when the half-life of elimination increased. We conclude that the crow is not susceptible to diclofenac and, more important, that toxicity in the Gyps species is probably related to zero-order metabolism.

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Section: In Vitro Toxicity Assaymentioning

confidence: 99%

The Pied Crow (Corvus Albus) Is Insensitive to Diclofenac at Concentrations Present in Carrion

Naidoo

Mompati

Duncan

et al. 2011

Journal of Wildlife Diseases

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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.…”

mentioning

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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“…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%

“…Specifically, in isolated liver mitochondria, diclofenac readily inhibits ATP synthesis and induces the MPT [94, 97], leading to a collapse of the mitochondrial transmembrane potential (ΔΨ m ). In this context, diclofenac, which is a lipophilic and weak acidic compound, works as an uncoupler of oxidative phosphorylation [101], translocating protons across the inner mitochondrial membrane to cause uncoupling.…”

Section: Diclofenac Hepatotoxicitymentioning

confidence: 99%

“…Apoptosis was observed after exposure to sub-cytotoxic concentrations of diclofenac, mediated by opening the MPT pore and increased ROS, with activation of caspase 3, 8 & 9. These changes were prevented by anti-oxidant treatment, implicating mitochondrial ROS in caspase activation and downstream induction of apoptosis [97, 99]. It was also recently shown that diclofenac treatment decreased mitochondrial membrane potential in both rat and human hepatocytes in vitro, accompanied by mitochondrial fragmentation due to decrease in the mitochondrial fusion protein Mfn1 [104].…”

Section: Diclofenac Hepatotoxicitymentioning

confidence: 99%

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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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Diclofenac induces apoptosis in hepatocytes by alteration of mitochondrial function and generation of ROS

Cited by 161 publications

References 52 publications

The Pied Crow (Corvus Albus) Is Insensitive to Diclofenac at Concentrations Present in Carrion

The Pied Crow (Corvus Albus) Is Insensitive to Diclofenac at Concentrations Present in Carrion

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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