Evaluación toxicológica de la 4-hidroxicumarina: Estudios (anti) mutagénicos, tóxicos y antioxidantes

Autores/as

DOI:

https://doi.org/10.33448/rsd-v10i8.16948

Palabras clave:

Antioxidante; Cumarinas; Genotoxicidad; Pruebas de Mutagenicidad.

Resumen

La 4-hidroxicumarina (4H) es un compuesto fenólico natural y sintético que presenta importantes atributos, que incluyen propiedades anti-VIH, antitumorales y anticoagulantes. Considerando sus importantes actividades biológicas y el uso de 4H, el objetivo de este estudio fue investigar las actividades tóxicas, mutagénicas, antimutagénicas y antioxidantes de 4H, obtenidas comercialmente, en experimentos in vivo e in vitro. Los efectos de la administración oral aguda a una dosis de 200 mg / kg de 4H se investigaron mediante el cribado hipocrático en animales. El ensayo de micronúcleos en sangre periférica y la prueba de Ames se utilizaron para el análisis de mutagenicidad, mientras que la antimutagenicidad se probó contra ciclofosfamida también mediante ensayo de micronúcleos in vivo. Para todas las pruebas in vivo se utilizaron ratones suizos. La actividad antioxidante se determinó por la capacidad de la muestra de 4H para secuestrar el radical estable 2,2-difenil-1-picrilhidrazilo (DPPH). Los resultados mostraron que 4H no indujo cambios en el comportamiento o la histología de los animales tratados ni actividad mutagénica (génica o cromosómica). Por otro lado, exhibió un efecto protector contra la ciclofosfamida y potencial antioxidante. La 4H se utiliza ampliamente en la clínica como molécula precursora en la síntesis de fármacos anticoagulantes sintéticos. Por tanto, los resultados obtenidos son de suma importancia, ya que demuestran la ausencia de potencial mutagénico y protección frente al daño cromosómico.

Citas

Abdelhafez, O. M., Amin, K. M., Batran, R. Z., Maher, T. J., Nada, S. A., & Sethumadhavan, S. (2010). Synthesis, anticoagulant and PIVKA-II induced by new 4-hydroxycoumarin derivatives. Bioorganic & Medicinal Chemistry, 18(10), 3371–3378. https://doi.org/10.1016/j.bmc.2010.04.009

Araújo, S. G., Pinto, M. E. A., Silva, N. L., Santos, F. J. L., Castro, A. H. F., & Lima, L. (2013). Antioxidant and allelopathic activities of extract and fractions from Rosmarinus officinalis. Biochemistry and Biotechnology Reports, 2(1), 35–43.

Bernstein, L., Kaldor, J., McCann, J., & Pike, M. C. (1982). An empirical approach to the statistical analysis of mutagenesis data from the Salmonella test. Mutation Research/Environmental Mutagenesis and Related Subjects, 97(4), 267–281.

Bode, A. M., & Dong, Z. (2000). Signal transduction pathways: targets for chemoprevention of skin cancer. The Lancet Oncology, 1(3), 181–188.

Botham, P. A. (2004). Acute systemic toxicity—prospects for tiered testing strategies. Toxicology in Vitro, 18(2), 227–230.

Cheng, S. X. (2016). Calcium-sensing receptor: a new target for therapy of diarrhea. World Journal of Gastroenterology, 22(9), 2711.

Clardy, J., & Walsh, C. (2004). Lessons from natural molecules. Nature, 432(7019), 829–837. https://doi.org/10.1038/nature03194

da Silva, D., Lopes, E. L., & Junior, S. S. B. (2014). Pesquisa quantitativa: elementos, paradigmas e definições. Revista de Gestão e Secretariado, 5(1), 1–18.

de Souza Marques, E., Salles, D. B., & Maistro, E. L. (2015). Assessment of the genotoxic/clastogenic potential of coumarin derivative 6, 7-dihydroxycoumarin (aesculetin) in multiple mouse organs. Toxicology Reports, 2, 268–274.

Dearfield, K. L., Cimino, M. C., McCarroll, N. E., Mauer, I., & Valcovic, L. R. (2002). Genotoxicity risk assessment: a proposed classification strategy. Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 521(1–2), 121–135.

Egan, D., O’kennedy, R., Moran, E., Cox, D., Prosser, E., & Thornes, R. D. (1990). The pharmacology, metabolism, analysis, and applications of coumarin and coumarin-related compounds. Drug Metabolism Reviews, 22(5), 503–529.

Evans, M. D., & Cooke, M. S. (2004). Factors contributing to the outcome of oxidative damage to nucleic acids. Bioessays, 26(5), 533–542.

Ezuruike, U. F., & Prieto, J. M. (2014). The use of plants in the traditional management of diabetes in Nigeria: Pharmacological and toxicological considerations. Journal of Ethnopharmacology, 155(2), 857–924.

FDA. (2012). Guidance for Industry: S2 (R1) Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use.

Fedato, Rafael Palhano, & Maistro, E. L. (2014). Absence of genotoxic effects of the coumarin derivative 4-methylesculetin in vivo and its potential chemoprevention against doxorubicin-induced DNA damage. Journal of Applied Toxicology, 34(1), 33–39. https://doi.org/10.1002/jat.2823

Finn, G. J., Kenealy, E., Creaven, B. S., & Egan, D. A. (2002). In vitro cytotoxic potential and mechanism of action of selected coumarins, using human renal cell lines. Cancer Letters, 183(1), 61–68.

Furtado, M. A., de Almeida, L. C., Furtado, R. A., Cunha, W. R., & Tavares, D. C. (2008). Antimutagenicity of rosmarinic acid in Swiss mice evaluated by the micronucleus assay. Mutat Res, 657(2), 150–154. https://doi.org/10.1016/j.mrgentox.2008.09.003

Fylaktakidou, K. C., Hadjipavlou-Litina, D. J., Litinas, K. E., & Nicolaides, D. N. (2004). Natural and synthetic coumarin derivatives with anti-inflammatory/antioxidant activities. Current Pharmaceutical Design, 10(30), 3813–3833.

Guideline, O. O. (2001). 425: acute oral toxicity—up-and-down procedure. OECD Guidelines for the Testing of Chemicals, 2, 12–16.

Gülçin, I. (2006). Antioxidant and antiradical activities of L-carnitine. Life Sciences, 78(8), 803–811. https://doi.org/10.1016/j.lfs.2005.05.103

Hayashi, M. (2016). The micronucleus test—most widely used in vivo genotoxicity test—. Genes and Environment, 38(1), 18. https://doi.org/10.1186/s41021-016-0044-x

Jaramillo-García, V., Trindade, C., Lima, E., Guecheva, T. N., Villela, I., Martinez-Lopez, W., Corrêa, D. S., Ferraz, A. B. F., Moura, S., Sosa, M. Q., Da Silva, J., & Henriques, J. A. P. (2018). Chemical characterization and cytotoxic, genotoxic, and mutagenic properties of Baccharis trinervis (Lam, Persoon) from Colombia and Brazil. J Ethnopharmacol, 213, 210–220. https://doi.org/10.1016/j.jep.2017.10.027

Kirkland, D., Reeve, L., Gatehouse, D., & Vanparys, P. (2011). A core in vitro genotoxicity battery comprising the Ames test plus the in vitro micronucleus test is sufficient to detect rodent carcinogens and in vivo genotoxins. Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 721(1), 27–73.

Krishna, G., & Hayashi, M. (2000). In vivo rodent micronucleus assay: protocol, conduct and data interpretation. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 455(1–2), 155–166.

Kumar, V., Ahmed, D., Verma, A., Anwar, F., Ali, M., & Mujeeb, M. (2013). Umbelliferone β-D-galactopyranoside from Aegle marmelos (L.) corr. an ethnomedicinal plant with antidiabetic, antihyperlipidemic and antioxidative activity. BMC Complementary and Alternative Medicine, 13(1), 273.

Lake, B. G. (1999). Coumarin metabolism, toxicity and carcinogenicity: relevance for human risk assessment. Food Chem Toxicol, 37(4), 423–453. https://www.ncbi.nlm.nih.gov/pubmed/10418958

MacGregor, J. T., Wehr, C. M., & Gould, D. H. (1980). Clastogen-induced micronuclei in peripheral blood erythrocytes: The basis of an improved micronucleus test. Environmental Mutagenesis, 2(4), 509–514. https://doi.org/10.1002/em.2860020408

Maistro, E. L., de Souza Marques, E., Fedato, R. P., Tolentino, F., da Silva, C. de A. C., Tsuboy, M. S. F., Resende, F. A., & Varanda, E. A. (2015). In vitro assessment of mutagenic and genotoxic effects of coumarin derivatives 6, 7-dihydroxycoumarin and 4-methylesculetin. Journal of Toxicology and Environmental Health, Part A, 78(2), 109–118.

Maron, D. M., & Ames, B. N. (1983). Revised methods for the Salmonella mutagenicity test. Mutat Res, 113(3–4), 173–215. https://www.ncbi.nlm.nih.gov/pubmed/6341825

Maryna L. Zinovieva, & Peter G. Zhminko. (2017). Single and Repeat Dose Toxicity Study of 7-Hydroxycoumarin, Ethanol, and Their Mixture in Rats. Journal of Pharmacy and Pharmacology, 5(5). https://doi.org/10.17265/2328-2150/2017.05.002

Masfria, Sumaiyah, & Dalimunthe, A. (2017). Antimutagenic Activity of Ethanol Extract of Rhaphidophora pinnata (L.f) Schott Leaves on Mice. Scientia Pharmaceutica, 85(1), 7. https://doi.org/10.3390/scipharm85010007

Mortelmans, K., & Zeiger, E. (2000). The Ames Salmonella/microsome mutagenicity assay. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 455(1–2), 29–60.

Mythilypriya, R., Shanthi, P., & Sachdanandam, P. (2007). Oral acute and subacute toxicity studies with Kalpaamruthaa, a modified indigenous preparation, on rats. Journal of Health Science, 53(4), 351–358.

O’Reilly, R. A. (1976). The Stereoselective Interaction of Warfarin and Metronidazole in Man. New England Journal of Medicine, 295(7), 354–357. https://doi.org/10.1056/NEJM197608122950702

Pereira, A. S., Shitsuka, D. M., Parreira, F. J., & Shitsuka, R. (2018). Metodologia da pesquisa científica.[e-book]. Santa Maria. Ed. UAB/NTE/UFSM. Disponível em: https://repositorio. ufsm. br/bitstream/handle ….

Porwal, M., Khan, N. A., & Maheshwari, K. K. (2017). Evaluation of acute and subacute oral toxicity induced by ethanolic extract of marsdenia tenacissima leaves in experimental rats. Scientia Pharmaceutica, 85(3). https://doi.org/10.3390/scipharm85030029

Sharma, S. D., Rajor, H. K., Chopra, S., & Sharma, R. K. (2005). Studies on structure activity relationship of some dihydroxy-4-methylcoumarin antioxidants based on their interaction with Fe (III) and ADP. Biometals, 18(2), 143–154.

Shen, X., Mahajani, M., Wang, J., Yang, Y., Yuan, Q., Yan, Y., & Lin, Y. (2017). Elevating 4-hydroxycoumarin production through alleviating thioesterase-mediated salicoyl-CoA degradation. Metab Eng, 42, 59–65. https://doi.org/10.1016/j.ymben.2017.05.006

Stanchev, S., Momekov, G., Jensen, F., & Manolov, I. (2008). Synthesis, computational study and cytotoxic activity of new 4-hydroxycoumarin derivatives. Eur J Med Chem, 43(4), 694–706. https://doi.org/10.1016/j.ejmech.2007.05.005

Su, C. H., Chen, L. J., Liao, J. F., & Cheng, J. T. (2013). Increase of phosphatase and tensin homolog by silymarin to inhibit human pharynx squamous cancer. Journal of Medicinal Food, 16(9), 778–784. https://doi.org/10.1089/jmf.2012.2534

Sun, D., Zhao, T., Wang, T., Wu, M., & Zhang, Z. (2020). Genotoxicity assessment of triclocarban by comet and micronucleus assays and Ames test. Environmental Science and Pollution Research, 27(7), 7430–7438.

Thaisrivongs, S., Romero, D. L., Tommasi, R. A., Janakiraman, M. N., Strohbach, J. W., Turner, S. R., Biles, C., Morge, R. R., Johnson, P. D., Aristoff, P. A., Tomich, P. K., Lynn, J. C., Horng, M.-M., Chong, K.-T., Hinshaw, R. R., Howe, W. J., Finzel, B. C., & Watenpaugh, K. D. (1996). Structure-Based Design of HIV Protease Inhibitors: 5,6-Dihydro-4-hydroxy-2-pyrones as Effective, Nonpeptidic Inhibitors. Journal of Medicinal Chemistry, 39(23), 4630–4642. https://doi.org/10.1021/jm960228q

Tsuboy, M. S., Marcarini, J. C., Ferreira, D. T., Ferraz, E. R. A., Chequer, F. M. D., Oliveira, D. P. de, Ribeiro, L. R., & Mantovani, M. S. (2010). Evaluation of extracts from Coccoloba mollis using the Salmonella/microsome system and in vivo tests. Genetics and Molecular Biology, 33(3), 542–548.

Vasconcelos, J. F., Teixeira, M. M., Barbosa-Filho, J. M., Agra, M. F., Nunes, X. P., Giulietti, A. M., Ribeiro-dos-Santos, R., & Soares, M. B. P. (2009). Effects of umbelliferone in a murine model of allergic airway inflammation. European Journal of Pharmacology, 609(1–3), 126–131.

Zendeboodi, F., Khorshidian, N., Mortazavian, A. M., & da Cruz, A. G. (2020). Probiotic: Conceptualization from a new approach. Current Opinion in Food Science.

Publicado

05/07/2021

Cómo citar

CRUZ, L. F. da; SANTOS, C. G.; GONÇALVES, T. P. R.; MARENA, G. D.; SOUZA, I. L. A.; LIMA, L. A. R. dos S.; CHEQUER, F. M. D. .; PINTO, F. C. H. .; NOGUEIRA, F. A. R.; ARAUJO, M. G. de F. . Evaluación toxicológica de la 4-hidroxicumarina: Estudios (anti) mutagénicos, tóxicos y antioxidantes. Research, Society and Development, [S. l.], v. 10, n. 8, p. e7910816948, 2021. DOI: 10.33448/rsd-v10i8.16948. Disponível em: https://rsdjournal.org/index.php/rsd/article/view/16948. Acesso em: 6 jul. 2024.

Número

Sección

Ciencias de la salud