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Microbial Metabolism of Atovaquone and Cytotoxicity of the Produced Phase I Metabolite

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Abstract

Background and Objectives

Atovaquone is a hydroxynaphthoquinone with selective action in the mitochondrial respiratory chain of malaria parasite. It is employed for both the treatment and prevention of malaria, in a combination with proguanil. The aim of this study was to elucidate the in vitro metabolites from atovaquone and to evaluate their cytotoxic activities.

Methods

The biotransformation of atovaquone was performed using Mucor rouxii NRRL 1894, Cunninghamella echinulata var. elegans ATCC 8688a and C. elegans ATCC 10028b, which have been reported as microbial models of mammalian drug metabolism. Experiments were also carried out with two probiotic strains from the human intestinal tract: Bifidobacterium sp. and Lactobacillus acidophilus. The phase I metabolite was isolated, its chemical structure was elucidated and its toxicity was evaluated using the neoplastic cell line SKBR-3 derived from human breast cancer and normal human fibroblast cell line GM07492-A. Cell cytotoxicity assays were also carried out with atovaquone.

Result

Only the fungi were able to convert atovaquone to metabolite trans-3-[4′-(4″-chlorophenyl)cyclohexyl)-1,2-dioxo-dihydro-1H-indene-3-carboxylic acid. The metabolite displayed 50 % inhibitory concentration (IC50) values of 110.20 ± 2.2 and 108.80 ± 1.5 µmol/L against breast cancer cell line SKBR-3 and fibroblasts cell line GM07492-A, respectively. The IC50 values of atovaquone were 282.30 ± 1.8 and 340.50 ± 1.4 µmol/L against breast cancer and normal fibroblasts cell lines, respectively.

Conclusions

The produced metabolite was more toxic than atovaquone and was not selective to normal or cancer cell lines. The present study is the first to report the production of atovaquone metabolite.

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References

  1. Pangarkar PA, Wanare RS, Tayde AM. Crystal modification of atovaquone in presence of polyethylene glycol (PEG) 4000. Int J Pharm Sci Rev. 2013;4(12):4632–41.

    Google Scholar 

  2. Dinter D, Gajski G, Garaj-Vrhovac V. An alkaline comet assay study on the antimalarial drug atovaquone in human peripheral blood lymphocytes: a study based on clinically relevant concentrations. J Appl Toxicol. 2013;33(1):56–62.

    Article  PubMed  Google Scholar 

  3. Kessl JJ, Moskalev NV, Gribble GW, Nasr M, Meshnick SR, Trumpower BL. Parameters determining the relative efficacy of hydroxy-naphthoquinone inhibitors of the cytochrome bc1 complex. Biochim Biophys Acta. 2007;1767(4):319–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Nixon GL, Moss DM, Shone AE, Lalloo DG, Fisher N, O’Neill PM, Ward SA, Biagini CA. Antimalarial pharmacology and therapeutics of atovaquone. J Antimicrob Chemother. 2013;68(5):977–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Srivastava IK, Vaidya AB. A Mechanism for the synergistic antimalarial action of atovaquone and proguanil. Antimicrob Agents Chemother. 1999;43(6):1334–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Jones K, Ward SA. Biguanide-Atovaquone synergy against Plasmodium falciparum in vitro. Antimicrob Agents Chemother. 2002;46(8):2700–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sek L, Boyd BJ, Charman WN, Porter CJ. Examination of the impact of a range of pluronic surfactants on the in vitro solubilization behavior and oral bioavailability of lipidic formulations of atovaquone. J Pharm Pharmacol. 2006;58:809–20.

    Article  CAS  PubMed  Google Scholar 

  8. Baramee A, Coppin A, Mortuaire M, Pelinski L, Tomavo S, Brocard J. Synthesis and in vitro activities of ferrocenic aminohydroxynaphthoquinones against Toxoplasma gondii and Plasmodium falciparum. Bioorg Med Chem. 2006;14(5):1294–302.

    Article  CAS  PubMed  Google Scholar 

  9. Zhou J, Duan L, Chen H, Ren X, Zhang Z, Zhou F, Liu J, Pei D, Ding K. Atovaquone derivatives as potent cytotoxic and apoptosis inducing agentes. Bioorg Med Chem Lett. 2009;19(17):5091–4.

    Article  CAS  PubMed  Google Scholar 

  10. Njuguna NM, Masimirembwa C, Chibale K. Identification and characterization of reactive metabolites in natural products-driven drug discovery. J Nat Prod. 2012;75(3):507–13.

    Article  CAS  PubMed  Google Scholar 

  11. Asha S, Vidyavathi M. Cunninghamella—a microbial model for drug metabolism studies—a review. Biotechnol Adv. 2009;27(1):16–29.

    Article  CAS  PubMed  Google Scholar 

  12. Ibrahim AK, Radwan MM, Ahmed SA, Slade D, Ross SA, ElSohly MA, Khan IA. Microbial metabolism of cannflavin A and B isolated from Cannabis sativa. Phytochemistry. 2010;71(8–9):1014–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ouzzani J, Servy C, Bloy C, Ducrocq C. Fungal metabolite of naftazone inhibits nitrite production by activated murine macrophages. Bioorg Med Chem Lett. 1995;5(16):1825–8.

    Article  Google Scholar 

  14. Parshikov IA, Freeman JP, Lay JO Jr, Beger RD, Williams AJ, Sutherland JB. Microbiological transformation of enrofloxacin by the fungus Mucor ramannianus. Appl Environ Microbiol. 2000;66(6):2664–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Alexandre V, Ladril S, Maurs M, Azerad R. Microbial models of animal drug metabolism Part 5. Microbial preparation of human hydroxylated metabolites of irbesartan. J Mol Catal B Enzym. 2004;29(1–6):173–9.

    Article  CAS  Google Scholar 

  16. Duan M, Huang H, Li X, Chen X, Zhong D. Assignments of 1H and 13C NMR spectral data for ondansetron and its two novel metabolites, 1-hydroxy-ondansetron diastereoisomers. Magn Reson Chem. 2006;44(10):972–5.

    Article  CAS  PubMed  Google Scholar 

  17. Silva EO, Furtado NAJC, Aleu J, Collado IG. Terpenoid biotransformations by Mucor species. Phytochem Rev. 2013;12(4):857–76.

    Article  CAS  Google Scholar 

  18. Meca G, Ritieni A, Mañes J. Reduction in vitro of the minor Fusarium mycotoxin beauvericin employing different strains of probiotic bactéria. Food Control. 2012;28(2):435–40.

    Article  CAS  Google Scholar 

  19. Silva EO, Carvalho TC, Parshikov IA, Santos RA, Emery FS, Furtado NAJC. Cytotoxicity of lapachol metabolites produced by probiotics. Lett Appl Microbiol. 2014;59(1):108–14.

    Article  CAS  Google Scholar 

  20. Jackson M, Karwoswski JP, Humphrey PE, Kohl WL, Barlow GJ, Tanaka SK. Calbistrins, novel antifungal agents produced by Penicillium restrictum. J Antibiot. 1993;46(1):34–8.

    Article  CAS  PubMed  Google Scholar 

  21. Rolan PE, Mercer AJ, Tate E, Benjamin I, Posner J. Disposition of atovaquone in humans. Antimicrob Agents Chemother. 1997;41(6):1319–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Kelly SL, Kelly DE. Microbial cytochromes P450: biodiversity and biotechnology. Where do cytochromes P450 come from, what do they do and what can they do for us? Phil Trans R Soc Lond Ser B Biol Sci. 2013;368(1612):1612–28.

    Article  Google Scholar 

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Acknowledgments

The authors are grateful to the University of São Paulo, Brazil, for providing technical support to carry out the experiments. Eliane O. Silva acknowledges CNPq and CAPES for scholarships awarded for PhD studies.

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Authors and Affiliations

  1. Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Avenida do Café, s/n, Ribeirão Preto, SP, 14040-903, Brazil

    Eliane de Oliveira Silva & Niege Araçari Jacometti Cardoso Furtado

  2. Universidade de Franca, Núcleo de Pesquisas em Ciências Exatas e Tecnológicas, Av. Dr. Armando Salles de Oliveira, 201, Franca, 14404-600, Brazil

    Natália dos Santos Gonçalves & Raquel Alves dos Santos

Authors
  1. Eliane de Oliveira Silva
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  2. Natália dos Santos Gonçalves
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  3. Raquel Alves dos Santos
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  4. Niege Araçari Jacometti Cardoso Furtado
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Corresponding author

Correspondence to Niege Araçari Jacometti Cardoso Furtado.

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Funding

“São Paulo Research Foundation” (FAPESP Grant 2011/21700-5), “Conselho Nacional de Desenvolvimento Científico e Tecnológico” (CNPq) and “Coordenacão de Aperfeiçoamento de Pessoal de Nível Superior” (CAPES).

Conflict of interest

The authors declare that they have no conflict of interest.

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de Oliveira Silva, E., dos Santos Gonçalves, N., Alves dos Santos, R. et al. Microbial Metabolism of Atovaquone and Cytotoxicity of the Produced Phase I Metabolite. Eur J Drug Metab Pharmacokinet 41, 645–650 (2016). https://doi.org/10.1007/s13318-015-0294-1

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  • DOI: https://doi.org/10.1007/s13318-015-0294-1

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