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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Boerma, Jan Simon Vermeulen, Nico P. E. Commandeur, Jan N. M. |
| Description | Country affiliation: Netherlands Author Affiliation: Boerma JS ( Division of Molecular Toxicology, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Faculty of Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.); Vermeulen NP ( Division of Molecular Toxicology, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Faculty of Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.); Commandeur JN ( Division of Molecular Toxicology, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Faculty of Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands. Electronic address: j.n.m.commandeur@vu.nl.) |
| Abstract | Reactive metabolites have been suggested to play a role in the idiosyncratic hepatotoxicity observed with diclofenac (DF). By structural identification of the GSH conjugates formed after P450-catalyzed bioactivation of DF, it was shown that three types of reactive intermediates were formed: p-benzoquinone imines, o-imine methide and arene-oxide. Recently, detection of 2'-(glutathion-S-yl)-deschloro-diclofenac (DDF-SG), resulting from chlorine substitution, suggested the existence of a fourth type of P450-dependent reactive intermediate whose inactivation by GSH is completely dependent on presence of glutathione S-transferase. In this study, fourteen recombinant cytochrome P450s and three flavin-containing monooxygenases were tested for their ability to produce oxidative DF metabolites and their corresponding GSH conjugates. Concerning the hydroxymetabolites and their GSH conjugates, results were consistent with previous studies. Unexpectedly, all tested recombinant P450s were able to form DDF-SG to almost similar extent. DDF-SG formation was found to be partially independent of NADPH and even occurred by heat-inactivated P450. However, product formation was fully dependent on both GSH and glutathione-S-transferase P1-1. DDF-SG formation was also observed in reactions with horseradish peroxidase in absence of hydrogen peroxide. Because DDF-SG was not formed by free iron, it appears that DF can be bioactivated by iron in hemeproteins. This was confirmed by DDF-SG formation by other hemeproteins such as hemoglobin. As a mechanism, we propose that DF is subject to heme-dependent one-electron oxidation. The resulting nitrogen radical cation, which might activate the chlorines of DF, then undergoes a GST-catalyzed nucleophilic aromatic substitution reaction in which the chlorine atom of the DF moiety is replaced by GSH. |
| File Format | HTM / HTML |
| ISSN | 00092797 |
| Volume Number | 207 |
| e-ISSN | 18727786 |
| Journal | Chemico-Biological Interactions |
| Language | English |
| Publisher | Elsevier |
| Publisher Date | 2014-01-25 |
| Publisher Place | Ireland |
| Access Restriction | One Nation One Subscription (ONOS) |
| Subject Keyword | Discipline Biochemistry Discipline Pharmacology Cytochrome P-450 Enzyme System Metabolism Diclofenac Analogs & Derivatives Electrons Glutathione Ascorbic Acid Pharmacology Chromatography, High Pressure Liquid Chemistry Hemeproteins Horseradish Peroxidase Humans Iron Metabolic Networks And Pathways Drug Effects Microsomes, Liver Oxidation-reduction Oxygenases Recombinant Proteins Time Factors Journal Article |
| Content Type | Text |
| Resource Type | Article |
| Subject | Medicine Toxicology |
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