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Research ArticleArticle

Biomarkers of Flutamide-Bioactivation and Oxidative Stress In Vitro and In Vivo

Marieke Teppner, Franziska Boess, Beat Ernst and Axel Pähler
Drug Metabolism and Disposition April 2016, 44 (4) 560-569; DOI: https://doi.org/10.1124/dmd.115.066522
Marieke Teppner
Roche Pharmaceutical Research and Early Development pRED, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland
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Franziska Boess
Roche Pharmaceutical Research and Early Development pRED, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland
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Beat Ernst
Roche Pharmaceutical Research and Early Development pRED, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland
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Axel Pähler
Roche Pharmaceutical Research and Early Development pRED, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland
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Abstract

The nonsteroidal androgen-receptor antagonist flutamide is associated with hepatic injury. Oxidative stress and reactive metabolite formation are considered contributing factors to liver toxicity. Here we have used flutamide as a model drug to study the generation of reactive drug metabolites that undergo redox cycling to induce oxidative stress (OS) in vitro and in vivo. Lipid peroxidation (LPO) markers, as well as genes regulated by the redox-sensitive Nrf2 pathway, have been identified as surrogates for the characterization of OS. These markers and metabolism biomarkers for drug bioactivation have been investigated to characterize drug-induced hepatic damage. Rat hepatocytes and in vivo studies showed that several LPO markers, namely the isoprostanes 15R-PD2, dihydro keto PE2, and iPF2α-VI, as well as hydroxynonenal mercapturic acid metabolites, had increased significantly by 24 hours after flutamide treatment from 4.9 to 15.3-fold in hepatocytes and from 2.6 to 31.0-fold in rat plasma. Induction of mRNA expression levels for Nrf2-regulated genes was evident as well, with heme oxygenase 1, glutathione-S-transferase π1 and NAD(P)H dehydrogenase showing a 3.6-, 4.1-, and 1.9-fold increase in hepatocytes and 5.6-, 7.5-, and 94.1-fold in rat liver. All effects were observed at drug concentrations that did not show overt liver toxicity. Addition of an in situ hydrogen peroxide–generating system to in vitro experiments demonstrated the formation of a reactive di-imine intermediate as the responsible metabolic pathway for the generation of OS. The dataset suggests that hepatic oxidative stress conditions can be mediated via metabolic activation and can be monitored with suitable biomarkers preceding the terminal damage.

Footnotes

    • Received August 12, 2015.
    • Accepted January 6, 2016.
  • ↵1 Current affiliation: Evotec AG, Essener Bogen 7, 22419 Hamburg, Germany, marieke.teppner{at}evotec.com.

  • ↵2 Current affiliation: Institute of Molecular Pharmacy, University of Basel, Klingenbergstrasse 50, CH-4040 Basel, Switzerland.

  • dx.doi.org/10.1124/dmd.115.066522.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (4)
Drug Metabolism and Disposition
Vol. 44, Issue 4
1 Apr 2016
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Research ArticleArticle

Flutamide Bioactivation Causes Oxidative Stress

Marieke Teppner, Franziska Boess, Beat Ernst and Axel Pähler
Drug Metabolism and Disposition April 1, 2016, 44 (4) 560-569; DOI: https://doi.org/10.1124/dmd.115.066522

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Research ArticleArticle

Flutamide Bioactivation Causes Oxidative Stress

Marieke Teppner, Franziska Boess, Beat Ernst and Axel Pähler
Drug Metabolism and Disposition April 1, 2016, 44 (4) 560-569; DOI: https://doi.org/10.1124/dmd.115.066522
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