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Research ArticleArticle

Enzymatic Reduction and Glutathione Conjugation of Benzoquinone Ansamycin Heat Shock Protein 90 Inhibitors: Relevance for Toxicity and Mechanism of Action

Wenchang Guo, Philip Reigan, David Siegel and David Ross
Drug Metabolism and Disposition October 2008, 36 (10) 2050-2057; DOI: https://doi.org/10.1124/dmd.108.022004
Wenchang Guo
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Philip Reigan
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David Siegel
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David Ross
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Abstract

Two-electron reduction of benzoquinone ansamycin (BA) heat shock protein (Hsp) 90 inhibitors by NAD(P)H:quinone oxidoreductase 1 (NQO1) to hydroquinone ansamycins (BAH2s) leads to greater Hsp90 inhibitory activity. BAs can also be metabolized by one-electron reductases and can interact with glutathione, reactions that have been associated with toxicity. Using a series of BAs, we investigated the stability of the BAH2s generated by NQO1, the ability of BAs to be metabolized by one-electron reductases, and their conjugation with glutathione. The BAs used were geldanamycin (GM), 17-(allylamino)-17-demethoxygeldanamycin (17AAG), 17-demethoxy-17-[[2-(dimethyl amino)ethyl]amino]-geldanamycin (17DMAG), 17-(amino)-17-demethoxygeldanamycin (17AG), and 17-demethoxy-17-[[2-(pyrrolidin-1-yl)ethyl]amino]-geldanamycin (17AEP-GA). The relative stabilities of BAH2s at pH 7.4 were GM hydroquinone > 17AAG hydroquinone > 17DMAG hydroquinone > 17AG hydroquinone and 17AEP-GA hydroquinone. Using human and mouse liver microsomes and either NADPH or NADH as cofactors, 17AAG had the lowest rate of one-electron reduction, whereas GM had the highest rate. 17DMAG demonstrated the greatest rate of redox cycling catalyzed by purified human cytochrome P450 reductase, whereas 17AAG again had the slowest rate. GM formed a glutathione adduct most readily followed by 17DMAG. The formation of glutathione adducts of 17AAG and 17AG were relatively slow in comparison. These data demonstrate that GM, the most hepatotoxic BAs in the series had a greater propensity to undergo redox cycling reactions catalyzed by hepatic one-electron reductases and markedly greater reactivity with thiols when compared with the least hepatotoxic analog 17AAG. Minimizing the propensity of BA derivatives to undergo one-electron reduction and glutathione conjugation while maximizing their two-electron reduction to stable Hsp90 inhibitory hydroquinones may be a useful strategy for optimizing the therapeutic index of BAs.

Footnotes

  • This study was supported by National Institutes of Health Grant R01-CA51210 and by a State of Colorado Bioscience, Development, and Evaluation grant.

  • The authors disclose a patent interest (patent pending) in hydroquinone ansamycins.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.108.022004.

  • ABBREVIATIONS: Hsp, heat shock protein; BA, benzoquinone ansamycin; GM, geldanamycin; 17AAG, 17-(allylamino)-17-demethoxygeldanamycin; 17DMAG, 17-demthoxy-17-[[2-(dimethylamino)ethyl]amino]-geldanamycin; NQO1, NAD(P)H:quinone oxidoreductase 1; BAH2, hydroquinone ansamycin; 17AG, 17-(amino)-17-demethoxygeldanamycin; GMH2, geldanamycin hydroquinone; 17AEP-GA, 17-demethoxy-17-[[2-(pyrrolidin-1-yl)ethyl]amino]-geldanamycin; ES936, 5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione; rh, recombinant human; HPLC, high-performance liquid chromatography; LC, liquid chromatography; MS, mass spectroscopy; 17AAGH2, 17-(allylamino)-17-demethoxygeldanamycin hydroquinone; GSH, reduced glutathione; ANOVA, analysis of variance; 17DMAGH2, 17-demthoxy-17-[[2-(dimethylamino)ethyl]amino]-geldanamycin hydroquinone; 17AEP-GAH2, 17-demethoxy-17-[[2-(pyrrolidin-1-yl)ethyl]amino]-geldanamycin hydroquinone.

    • Received April 23, 2008.
    • Accepted July 16, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (10)
Drug Metabolism and Disposition
Vol. 36, Issue 10
1 Oct 2008
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Research ArticleArticle

Enzymatic Reduction and Glutathione Conjugation of Benzoquinone Ansamycin Heat Shock Protein 90 Inhibitors: Relevance for Toxicity and Mechanism of Action

Wenchang Guo, Philip Reigan, David Siegel and David Ross
Drug Metabolism and Disposition October 1, 2008, 36 (10) 2050-2057; DOI: https://doi.org/10.1124/dmd.108.022004

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Research ArticleArticle

Enzymatic Reduction and Glutathione Conjugation of Benzoquinone Ansamycin Heat Shock Protein 90 Inhibitors: Relevance for Toxicity and Mechanism of Action

Wenchang Guo, Philip Reigan, David Siegel and David Ross
Drug Metabolism and Disposition October 1, 2008, 36 (10) 2050-2057; DOI: https://doi.org/10.1124/dmd.108.022004
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