Simulation of interindividual differences in inactivation of reactive para -benzoquinone imine metabolites of diclofenac by glutathione S -transferases in human liver cytosol

Braver, Michiel W. den; Zhang, Yongjie; Venkataraman, Harini; Vermeulen, Nico; Commandeur, Jan N. M.

doi:10.1016/j.toxlet.2016.05.015

Cited by 20 publications

(23 citation statements)

References 42 publications

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“…Here, we evidenced that not only the metabolism of diclofenac by CYP2C9 and CYP3A4, but also glucuronidation by UGT2B7 is critical for its hepatotoxicity due to the formation of reactive metabolites (Tang 2003 ). The fact that these enzymes showed wide interindividual variability could contribute to patients’ different susceptibility to idiosyncratic hepatotoxicity induced by diclofenac (den Braver et al 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Customised in vitro model to detect human metabolism-dependent idiosyncratic drug-induced liver injury

et al. 2017

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Drug-induced liver injury (DILI) has a considerable impact on human health and is a major challenge in drug safety assessments. DILI is a frequent cause of liver injury and a leading reason for post-approval drug regulatory actions. Considerable variations in the expression levels of both cytochrome P450 (CYP) and conjugating enzymes have been described in humans, which could be responsible for increased susceptibility to DILI in some individuals. We herein explored the feasibility of the combined use of HepG2 cells co-transduced with multiple adenoviruses that encode drug-metabolising enzymes, and a high-content screening assay to evaluate metabolism-dependent drug toxicity and to identify metabolic phenotypes with increased susceptibility to DILI. To this end, HepG2 cells with different expression levels of specific drug-metabolism enzymes (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, GSTM1 and UGT2B7) were exposed to nine drugs with reported hepatotoxicity. A panel of pre-lethal mechanistic parameters (mitochondrial superoxide production, mitochondrial membrane potential, ROS production, intracellular calcium concentration, apoptotic nuclei) was used. Significant differences were observed according to the level of expression and/or the combination of several drug-metabolism enzymes in the cells created ad hoc according to the enzymes implicated in drug toxicity. Additionally, the main mechanisms implicated in the toxicity of the compounds were also determined showing also differences between the different types of cells employed. This screening tool allowed to mimic the variability in drug metabolism in the population and showed a highly efficient system for predicting human DILI, identifying the metabolic phenotypes associated with increased DILI risk, and indicating the mechanisms implicated in their toxicity.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-017-2036-4) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Customised in vitro model to detect human metabolism-dependent idiosyncratic drug-induced liver injury

et al. 2017

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“… 76 , 77 Under the conditions used in this study, up to 5 μM of 5-hydroxydiclofenac quinone imine could be trapped with GSH combined with GST. 78 Inactivation of NQO2 as a result of covalent modification by 5-hydroxydiclofenac quinone imine might therefore contribute to, but not account for, the lack of NQO2 activity. It can be argued that NQO2, in contrast to NQO1, is a preferential protein target for adduction of reactive drug metabolites and thereby further fulfills a detoxicating function.…”

Section: Discussionmentioning

confidence: 99%

Reduction and Scavenging of Chemically Reactive Drug Metabolites by NAD(P)H:Quinone Oxidoreductase 1 and NRH:Quinone Oxidoreductase 2 and Variability in Hepatic Concentrations

Braver-Sewradj

Braver

Toorneman

et al. 2018

Chem. Res. Toxicol.

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Detoxicating enzymes NAD(P)H:quinone oxidoreductase 1 (NQO1) and NRH:quinone oxidoreductase 2 (NQO2) catalyze the two-electron reduction of quinone-like compounds. The protective role of the polymorphic NQO1 and NQO2 enzymes is especially of interest in the liver as the major site of drug bioactivation to chemically reactive drug metabolites. In the current study, we quantified the concentrations of NQO1 and NQO2 in 20 human liver donors and NQO1 and NQO2 activities with quinone-like drug metabolites. Hepatic NQO1 concentrations ranged from 8 to 213 nM. Using recombinant NQO1, we showed that low nM concentrations of NQO1 are sufficient to reduce synthetic amodiaquine and carbamazepine quinone-like metabolites in vitro. Hepatic NQO2 concentrations ranged from 2 to 31 μM. NQO2 catalyzed the reduction of quinone-like metabolites derived from acetaminophen, clozapine, 4′-hydroxydiclofenac, mefenamic acid, amodiaquine, and carbamazepine. The reduction of the clozapine nitrenium ion supports association studies showing that NQO2 is a genetic risk factor for clozapine-induced agranulocytosis. The 5-hydroxydiclofenac quinone imine, which was previously shown to be reduced by NQO1, was not reduced by NQO2. Tacrine was identified as a potent NQO2 inhibitor and was applied to further confirm the catalytic activity of NQO2 in these assays. While the in vivo relevance of NQO2-catalyzed reduction of quinone-like metabolites remains to be established by identification of the physiologically relevant co-substrates, our results suggest an additional protective role of the NQO2 protein by non-enzymatic scavenging of quinone-like metabolites. Hepatic NQO1 activity in detoxication of quinone-like metabolites becomes especially important when other detoxication pathways are exhausted and NQO1 levels are induced.

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“…; den Braver et al. ). Due to the fact that numerous drug metabolites are detected in higher amounts in different habitats, the FDA (Food and Drug Administration) issued guidelines in 2008 for drug safety testing.…”

Section: Introductionmentioning

confidence: 99%

“…). As a result, a continuously growing consumption and deposition is being generated in the environment, in particular in aquatic systems (Robison and Jacobs ; den Braver et al ). NSAIDs and their degradation intermediates can have major ecological implications, which can lead to unpredictable effects on nature, aquatic organisms and mammals.…”

Section: Introductionmentioning

confidence: 99%

Oxyfunctionalization of nonsteroidal anti‐inflammatory drugs by filamentous‐fungi

et al. 2019

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Aims:We aimed to expand the microbial biocatalyst platform to generate essential oxyfunctionalized standards for pharmaceutical, toxicological and environmental research. In particular, we examined the production of oxyfunctionalized nonsteroidal anti-inflammatory drugs (NSAIDs) by filamentous-fungi. Methods and Results: Four NSAIDs; diclofenac, ibuprofen, naproxen and mefenamic acid were used as substrates for oxyfunctionalization in a biocatalytic process involving three filamentous-fungi strains; Beauveria bassiana, Clitocybe nebularis and Mucor hiemalis. Oxyfunctionalized metabolites that are major degradation intermediates formed by Cytochrome P450 monooxygenases in human metabolism were produced in isolated yields of up to 99% using 1 g l À1 of substrate. In addition, a novel compound, 3 0 ,4 0dihydroxydiclofenac, was produced by B. bassiana. Proteomic analysis identified CYP548A5 that might be responsible for diclofenac oxyfunctionalization in B. bassiana. Conclusions: Efficient fungi catalysed oxyfunctionalization was achieved when using NSAIDs as substrates. High purities and isolated yields of the produced metabolites were achieved. Significance and Impact of the Study: The lack of current efficient synthetic strategies for oxyfunctionalization of NSAIDs is a bottleneck to perform pharmacokinetic, pharmacodynamic and toxicological analysis for the pharmaceutical industry. Additionally, oxyfunctionalized derivatives are needed for tracking the fate and impact of such metabolites in the environment. Herein, we described a fungi catalysed process that surpasses previously reported strategies in terms of efficiency, to synthesize oxyfunctionalized NSAIDs.

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Simulation of interindividual differences in inactivation of reactive para -benzoquinone imine metabolites of diclofenac by glutathione S -transferases in human liver cytosol

Cited by 20 publications

References 42 publications

Customised in vitro model to detect human metabolism-dependent idiosyncratic drug-induced liver injury

Customised in vitro model to detect human metabolism-dependent idiosyncratic drug-induced liver injury

Reduction and Scavenging of Chemically Reactive Drug Metabolites by NAD(P)H:Quinone Oxidoreductase 1 and NRH:Quinone Oxidoreductase 2 and Variability in Hepatic Concentrations

Oxyfunctionalization of nonsteroidal anti‐inflammatory drugs by filamentous‐fungi

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