Monensin A is a commercially important natural product isolated from Streptomyces cinnamonensins that is primarily employed to treat coccidiosis. Monensin A selectively complexes and transports sodium cations across lipid membranes and displays a variety of biological properties. In this study, we evaluated the Jacobsen catalyst as a cytochrome P450 biomimetic model to investigate the oxidation of monensin A. Mass spectrometry analysis of the products from these model systems revealed the formation of two products: 3-O-demethyl monensin A and 12-hydroxy monensin A, which are the same ones found in in vivo models. Monensin A and products obtained in biomimetic model were tested in a mitochondrial toxicity model assessment and an antimicrobial bioassay against Staphylococcus aureus, S. aureus methicillin-resistant, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Escherichia coli. Our results demonstrated the toxicological effects of monensin A in isolated rat liver mitochondria but not its products, showing that the metabolism of monensin A is a detoxification metabolism. In addition, the antimicrobial bioassay showed that monensin A and its products possessed activity against Gram-positive microorganisms but not for Gram-negative microorganisms. The results revealed the potential of application of this biomimetic chemical model in the synthesis of drug metabolites, providing metabolites for biological tests and other purposes.

Departamento de Análises Clínicas Toxicológicas e Bromatológicas Faculdade de Ciências Farmacêuticas de Ribeirão Preto Universidade de São Paulo 14040 903 Ribeirão Preto SP Brazil

Departamento de Química Faculdade de Filosofia Ciências e Letras de Ribeirão Preto Universidade de São Paulo 14040 901 Ribeirão Preto SP Brazil

Institute of Microbiology Academy of Sciences of the Czech Republic Vídeňská CZ 142 20 Prague Czech Republic

Laboratório de Pesquisa Desenvolvimento e Inovação Apis Flora Industrial e Comercial LTDA 140120 670 Ribeirão Preto SP Brazil

Núcleo de Pesquisas em Produtos Naturais e Sintéticos Faculdade de Ciências Farmacêuticas de Ribeirão Preto Universidade de São Paulo 14040 903 Ribeirão Preto SP Brazil

School of Chemistry University of Bristol Bristol BS8 1TS UK

Zobrazit více v PubMed

Huczyński A, Stefańska J, Przybylski P, Brzezinski B, Bartl F. Synthesis and antimicrobial properties of Monensin A esters. Bioorganic and Medicinal Chemistry Letters. 2008;18(8):2585–2589. PubMed

Huczyński A, Ratajczak-Sitarz M, Stefańska J, Katrusiak A, Brzezinski B, Bartl F. Reinvestigation of the structure of monensin A phenylurethane sodium salt based on X-ray crystallographic and spectroscopic studies, and its activity against hospital strains of methicillin-resistant S. epidermidis and S. aureus . Journal of Antibiotics. 2011;64(3):249–256. PubMed

Huczyński A. Polyether ionophores—promising bioactive molecules for cancer therapy. Bioorganic and Medicinal Chemistry Letters. 2012;22(23):7002–7010. PubMed

Łowicki D, Huczyński A. Structure and antimicrobial properties of monensin a and its derivatives: summary of the achievements. BioMed Research International. 2013;2013:14 pages.742149 PubMed PMC

Adovelande J, Schrével J. Carboxylic ionophores in malaria chemotherapy: the effects of monensin and nigericin on Plasmodium falciparum in vitro and Plasmodium vinckei petteri in vivo . Life Sciences. 1996;59(20):PL309–PL315. PubMed

Surolia R, Pachauri M, Ghosh PC. Preparation and characterization of monensin loaded PLGA nanoparticles: in vitro anti-malarial activity against Plasmodium falciparum . Journal of Biomedical Nanotechnology. 2012;8(1):172–181. PubMed

Rosén J. Efficient and sensitive screening and confirmation of residues of selected polyether ionophore antibiotics in liver and eggs by liquid chromatography-electrospray tandem mass spectrometry. Analyst. 2001;126(11):1990–1995. PubMed

Rokka M, Peltonen K. Simultaneous determination of four coccidiostats in eggs and broiler meat: validation of an LC-MS/MS method. Food Additives and Contaminants A: Chemistry Analysis Control Exposure & Risk Assessment. 2006;23(5):470–478. PubMed

Moloney M, Clarke L, O’Mahony J, Gadaj A, O’Kennedy R, Danaher M. Determination of 20 coccidiostats in egg and avian muscle tissue using ultra high performance liquid chromatography-tandem mass spectrometry. Journal of Chromatography A. 2012;1253:94–104. PubMed

Caldeira C, Neves WS, Cury PM, Serrano P, Baptista MASF, Burdmann EA. Rhabdomyolysis, acute renal failure, and death after monensin ingestion. The American Journal of Kidney Diseases. 2001;38(5):1108–1112. PubMed

Kouyoumdjian JA, Da Penha Ananias Morita M, Sato AK, Pissolatti AF. Fatal rhabdomyolysis after acute sodium monensin (Rumensin) toxicity: case report. Arquivos de Neuro-Psiquiatria. 2001;59(3):596–598. PubMed

Souza AC, Machado FS, Celes MRN, et al. Mitochondrial damage as an early event of monensin-induced cell injury in cultured fibroblasts L929. Journal of Veterinary Medicine Series A: Physiology Pathology Clinical Medicine. 2005;52(5):230–237. PubMed

Mansuy D. Brief historical overview and recent progress on cytochromes P450: adaptation of aerobic organisms to their chemical environment and new mechanisms of prodrug bioactivation. Annales Pharmaceutiques Francaises. 2011;69(1):62–69. PubMed

Ortiz-Montellano PR. Cytochrome P450: Structure, Mechanism, and Biochemistry. New York, NY, USA: Plenum Press; 2004.

Mac Leod TCO, Faria AL, Barros VP, Queiroz MEC, Assis MD. Primidone oxidation catalyzed by metalloporphyrins and Jacobsen catalyst. Journal of Molecular Catalysis A: Chemical. 2008;296(1-2):54–60.

Leod TCOM, Barros VP, Faria AL, et al. Jacobsen catalyst as a P450 biomimetic model for the oxidation of an antiepileptic drug. Journal of Molecular Catalysis A: Chemical. 2007;273(1-2):259–264.

Niehues M, Barros VP, Emery FDS, Dias-Baruffi M, Assis MDD, Lopes NP. Biomimetic in vitro oxidation of lapachol: a model to predict and analyse the in vivo phase i metabolism of bioactive compounds. European Journal of Medicinal Chemistry. 2012;54:804–812. PubMed

De Santis Ferreira L, Callejon DR, Engemann A, et al. In vitro metabolism of grandisin, a lignan with anti-chagasic activity. Planta Medica. 2012;78(18):1939–1941. PubMed

Bernadou J, Meunier B. Biomimetic chemical catalysts in the oxidative activation of drugs. Advanced Synthesis and Catalysis. 2004;346(2-3):171–184.

Lohmann W, Karst U. Biomimetic modeling of oxidative drug metabolism: strategies, advantages and limitations. Analytical and Bioanalytical Chemistry. 2008;391(1):79–96. PubMed

Rocha BA, Assis MD, Peti APF, et al. In vitro metabolism of monensin A: microbial and human liver microsomes models. Xenobiotica. 2014;44:326–335. PubMed

Sousa-Junior JN, Rocha BA, Assis MD, et al. Biomimetic oxidation studies of monensin A catalyzed by metalloporphyrins: identification of hydroxyl derivative product by electrospray tandem mass spectrometry. Brazilian Journal of Pharmacognosy. 2013;23:621–629.

Andrews JM. Determination of minimum inhibitory concentrations. Journal of Antimicrobial Chemotherapy. 2001;48:5–16. PubMed

Furtado NAJC, Said S, Ito IY, Bastos JK. The antimicrobial activity of Aspergillus fumigatus is enhanced by a pool of bacteria. Microbiological Research. 2002;157(3):207–211. PubMed

Pereira LC, De Souza AO, Dorta DJ. Polybrominated diphenyl ether congener (BDE-100) induces mitochondrial impairment. Basic and Clinical Pharmacology and Toxicology. 2013;112(6):418–424. PubMed

Chance B, Willians GR. The respiratory chain and oxidative phosphorylation. Advances in Enzymology and Related Subjects of Biochemistry. 1956;17:65–134. PubMed

Cathcart R, Schwiers E, Ames BN. Detection of picomole levels of hydroperoxides using a fluorescent dichlorofluorescein assay. Analytical Biochemistry. 1983;134(1):111–116. PubMed

Lopes NP, Stark CBW, Gates PJ, Staunton J. Fragmentation studies on monensin A by sequential electrospray mass spectrometry. Analyst. 2002;127(4):503–506. PubMed

Lopes NP, Stark CBW, Hong H, Gates PJ, Staunton J. Fragmentation studies on monensin A and B by accuratemass electrospray tandem mass spectrometry. Rapid Communications in Mass Spectrometry. 2002;16(5):414–420. PubMed

Otera H, Wang C, Cleland MM, et al. Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells. Journal of Cell Biology. 2010;191(6):1141–1158. PubMed PMC

Lemasters JJ. Mechanisms of hepatic toxicity. V. Necrapoptosis and the mitochondrial permeability transition: shared pathways to necrosis and apoptosis. The American Journal of Physiology—Gastrointestinal and Liver Physiology. 1999;276(1):1–6. PubMed

Rana A, Rera M, Walker DW. Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan. Proceedings of the National Academy of Sciences of the United States of America. 2013;110(21):8638–8643. PubMed PMC

Garcia AF, Medeiros HCD, Maioli MA, et al. Comparative effects of lantadene A and its reduced metabolite on mitochondrial bioenergetics. Toxicon. 2010;55(7):1331–1337. PubMed

Pereira LC, Souza AO, Pazin M, et al. Mitocôndria como alvo para avaliação de toxicidade de xenobiótico. Revista Brasileira de Toxicologia. 2012;25:1–14.

Garrison EM, Arrizabalaga G. Disruption of a mitochondrial MutS DNA repair enzyme homologue confers drug resistance in the parasite Toxoplasma gondii . Molecular Microbiology. 2009;72(2):425–441. PubMed PMC

Mollenhauer HH, Morré DJ, Rowe LD. Alteration of intracellular traffic by monensin; mechanism, specificity and relationship to toxicity. Biochimica et Biophysica Acta. 1990;1031(2):225–246. PubMed PMC

Ketola K, Vainio P, Fey V, Kallioniemi O, Iljin K. Monensin is a potent inducer of oxidative stress and inhibitor of androgen signaling leading to apoptosis in prostate cancer cells. Molecular Cancer Therapeutics. 2010;9(12):3175–3185. PubMed

Singh M, Kalla NR, Sanyal SN. Effect of monensin, a Na+-specific carboxylic ionophore on the oxidative defense system in rat testis. Pharmacological Reports. 2007;59(4):456–461. PubMed

Mingatto FE, Rodrigues T, Pigoso AA, Uyemura SA, Curti C, Santos AC. The critical role of mitochondrial energetic impairment in the toxicity of nimesulide to hepatocytes. Journal of Pharmacology and Experimental Therapeutics. 2002;303(2):601–607. PubMed

Kowaltowski AJ, Castilho RF, Vercesi AE. Mitochondrial permeability transition and oxidative stress. FEBS Letters. 2001;495(1-2):12–15. PubMed

Donoho AL. Biochemical studies on the fate of monensin in animals and in the environment. Journal of Animal Science. 1984;58(6):1528–1539. PubMed

Sassman SA, Lee LS. Sorption and degradation in soils of veterinary ionophore antibiotics: monensin and lasalocid. Environmental Toxicology and Chemistry. 2007;26(8):1614–1621. PubMed

Johnson DC, Spear PG. Monensin inhibits the processing of herpes simplex virus glycoproteins, their transport to the cell surface, and the egress of virions from infected cells. Journal of Virology. 1982;43(3):1102–1112. PubMed PMC