Metabolism related toxicity of diclofenac in yeast as model system

Leeuwen, Jolanda van; Vredenburg, Galvin; Dragović, Sanja; Tjong, T.F. Jennifer; Vos, J. Chris; Vermeulen, Nico

doi:10.1016/j.toxlet.2010.11.010

Cited by 41 publications

(40 citation statements)

References 36 publications

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“…Interestingly, ROS formation in adapted cells incubated with 50 M diclofenac was significantly lower than that in freshly treated cells. As we have observed previously (43,44), there is a clear correlation between diclofenac-induced growth inhibition and ROS formation.…”

Section: Resultssupporting

confidence: 85%

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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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Section: Resultssupporting

confidence: 85%

“…Previously, we have shown in Saccharomyces cerevisiae that subunits Rip1p and Cox9p of the mitochondrial respiratory chain are diclofenac targets and that metabolism of diclofenac by cytochrome P450s increases its toxicity (43,44). Yeast is an excellent eukaryotic model organism for toxicological research (20,45).…”

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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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“…It also reduces their ability to bind to solids which can be very significant for non-polar compounds, as shown for the NSAID mefenamic acid by (Jones et al, 2005). Also, hydroxylated compounds can have reduced toxicity compared to the original metabolite, as shown in the case of hydroxy-diclofenac metabolites in a yeast system (van Leeuwen et al, 2011). In other cases, however, the hydroxy metabolites have been proven to be more toxic than the original compound.…”

Section: Introductionmentioning

confidence: 99%

Efficient biotransformation of non-steroid anti-inflammatory drugs by endophytic and epiphytic fungi from dried leaves of a medicinal plant, Plantago lanceolata L.

Gonda

Kiss‐Szikszai

Szűcs

et al. 2016

International Biodeterioration & Biodegradation

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In the current study, decomposition of diclofenac, diflunisal, ibuprofen, mefenamic acid and piroxicam was tested using nine identified strains of endophytic and epiphytic fungi (from Ascomycota) adapted to natural products resembling the pharmaceuticals. The strains were isolated from a medicinal plant, Plantago lanceolata leaves. Metabolites were tentatively identified by liquid chromatography -tandem mass spectrometry ).Eighteen of the 45 combinations resulted in significant decrease of the concentration of the NSAIDs in model solutions. The most active strains were Aspergillus nidulans and Bipolaris tetramera, while Epicoccum nigrum and Aspergillus niger showed somewhat less potency. Piroxicam and diclofenac were most resistant to biotransformation, while ibuprofen and mefenamic acid were efficiently metabolized by most strains. Ten metabolites could be tentatively identified, includinghydroxy-metabolites of all tested NSAIDs, and a dihydroxy-metabolite of piroxicam. This biotransformation is likely to modify the toxicity and bioaccumulation potential of these pharmaceuticals.The results highlight the applicability of polyphenol-rich dried medicinal plant materials as an excellent source of fungi with high biotransforming potential. The results also suggest more in-depth testing of these fungi for biodegradation processes.

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“…Dic is metabolized to Dic-AG by UGT2B7 and to 49-hydroxy Dic (49-OH Dic) and 5-hydroxy Dic (5-OH Dic) by CYP2C9 and CYP3A4, respectively, in humans. It has been reported that these hydroxides are potential protoxicants because they can be further oxidized to quinone imine (van Leeuwen et al, 2011). To investigate whether Dic-AG and other metabolites might increase the expression levels of IL-8 and MCP-1 and decrease the CD14 + cell population in PBMCs, PBMCs were treated with 100 mM Dic-AG, 49-OH Dic, or 5-OH Dic for 24 hours, and the IL-8 and MCP-1 mRNA levels and the cell viability of CD3 + , CD14 + , and CD19 + cells were then measured.…”

Section: Resultsmentioning

confidence: 99%

Evaluation and Mechanistic Analysis of the Cytotoxicity of the Acyl Glucuronide of Nonsteroidal Anti-Inflammatory Drugs

et al. 2013

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The chemical reactivity of acyl glucuronide (AG) has been thought to be associated with the toxic properties of drugs containing carboxylic acid moieties, but there has been no direct evidence showing that AG formation is related to the observed toxicity. In the present study, the cytotoxicity of AGs, especially that associated with the inflammatory response, was investigated. The changes in the mRNA and protein expression levels of interleukin 8 (IL-8) and monocyte chemoattractant protein (MCP)-1 induced by the treatment of human peripheral blood mononuclear cells (PBMCs) with diclofenac (Dic), probenecid (Pro), tolmetin (Tol), ibuprofen (Ibu), naproxen (Nap), and their AGs were investigated by real-time reverse transcription polymerase chain reaction, and the viabilities of CD3+, CD14+, and CD19+ cells were measured by flow cytometry. Treatment with Dic-AG, Pro-AG, and Tol-AG significantly increased the expression levels of IL-8 and MCP-1. In addition, Dic-AG, Pro-AG, and Tol-AG significantly decreased the viability of CD14+ cells. Of these three AGs, Dic-AG showed the most potent changes, followed by Tol-AG and Pro-AG. Treatment with Ibu-AG and Nap-AG affected neither the expression levels of IL-8 and MCP-1 nor the viability of CD14+ cells. None of the drugs affected the CD3+ and CD19+ cell populations. Dic-AG increased the phosphorylation of p38 mitogen-activated protein (MAP) kinase and c-Jun N-terminal kinase (JNK)1/2. The pretreatment of peripheral blood mononuclear cells (PBMCs) with SB203580 (p38 inhibitor) significantly suppressed the Dic-AG-induced expression of inflammatory factors and cytotoxicity of CD14+ cells. In conclusion, AGs induce inflammatory responses and cytotoxicity against CD14+ cells via the p38 MAPK pathway. These factors may be useful biomarkers for evaluating the toxicity of AGs.

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Metabolism related toxicity of diclofenac in yeast as model system

Cited by 41 publications

References 36 publications

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

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

Efficient biotransformation of non-steroid anti-inflammatory drugs by endophytic and epiphytic fungi from dried leaves of a medicinal plant, Plantago lanceolata L.

Evaluation and Mechanistic Analysis of the Cytotoxicity of the Acyl Glucuronide of Nonsteroidal Anti-Inflammatory Drugs

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