ORIGINAL_ARTICLE The combination of immunomodulators and antibiotics in the treatment of animals with diseases of bacterial etiology is one of the effective strategies for animal therapy. The drug gentabiferon-B combines antibiotic gentamicin and speciesspecific (bovine) recombinant interferons -α and -γ. The study aimed to evaluate the effect of course application of gentabiferon-B on the cytogenetic stability of bone marrow cells of outbred mice after administering mitomycin C (MMC). The proportion of polychromatophilic erythrocytes in the bone marrow was assessed. There was no effect of gentabiferon-B on the frequency of polychromatophilic erythrocytes with micronuclei in both healthy animals and mice with MMC-induced cytogenetic instability. The course application of gentabiferon-B before the administration of MMC led to an increase in the proportion of polychromatophilic erythrocytes (46.03±2.61%) which was non-significantly different than the negative control group. The administration of MMC alone caused a decrease in the proportion of polychromatophilic erythrocytes to 33.33±1.83%. The antitoxic effect of gentabiferon-B led to an increase in the level of polychromatophilic erythrocytes by 38.1% compared to the group that received only MMC. Studies have shown that gentabiferon-B does not have mutagenic activity and anticlastogenic properties, however, it reduces the toxic effect of MMC. In conclusion, it is indicative that gentabiferon-B has antitoxic properties and can be safely used in animal therapy. https://macvetrev.mk/Files/Article/2022/10.2478/macvetrev-2022-0016/macvetrev-2022-0016.pdf 2022-03-15T09:00:00 79 87 10.2478/macvetrev-2022-0016 gentabiferon-B micronucleus test mitomycin mutagenicity Sergey Shabunin false 1 Department of Experimental Pharmacology, FSBSI, All-Russian Scientific Research Veterinary Institute of Pathology, Pharmacology and Therapy, 114-B Lomonosova, Voronezh 394087, Russia AUTHOR Vasilina Gritsyuk false 2 Department of Experimental Pharmacology, FSBSI, All-Russian Scientific Research Veterinary Institute of Pathology, Pharmacology and Therapy, 114-B Lomonosova, Voronezh 394087, Russia AUTHOR Galina Vostroilova false 3 Department of Experimental Pharmacology, FSBSI, All-Russian Scientific Research Veterinary Institute of Pathology, Pharmacology and Therapy, 114-B Lomonosova, Voronezh 394087, Russia AUTHOR Dmitriy Shabanov false 4 Department of Experimental Pharmacology, FSBSI, All-Russian Scientific Research Veterinary Institute of Pathology, Pharmacology and Therapy, 114-B Lomonosova, Voronezh 394087, Russia AUTHOR Nina Khokhlova nina_xoxlova@mail.ru false 5 Department of Experimental Pharmacology, FSBSI, All-Russian Scientific Research Veterinary Institute of Pathology, Pharmacology and Therapy, 114-B Lomonosova, Voronezh 394087, Russia LEAD_AUTHOR Anastasiya Korchagina false 6 Department of Experimental Pharmacology, FSBSI, All-Russian Scientific Research Veterinary Institute of Pathology, Pharmacology and Therapy, 114-B Lomonosova, Voronezh 394087, Russia AUTHOR Miroshnikova, M.S. (2021). Study of the potentiated effect of antimicrobial drugs against probiotic strains of microorganisms. Izvestia Orenburg State Agrarian University 2(88): 168-173. [in Russian] 1 10.37670/2073-0853-2021-88-2-168-173 Vostroilova, G.A., Shakhov, A.G., Shabunin, S.V., Sashnina, L.Yu., Parshin, P.A., Cheskidova, L.V., Kantorovich, Yu.A. (2018). Сorrective influence of hentabiferon-С on the immune status of postweaned piglets snd its rffectiveness in the prevention of intestinal infections. Russ Agric Sci. 6, 58-61. 2 Cheskidova, L.V., Briukhova, I.V., Grigoreva, N.A. (2019). Advanced research directions of creation of new generation medicines for animals with application of biotechnologies (Review). Bulletin Vet Pharmacol. 2(7): 29-38. [in Russian] 3 10.17238/issn2541-8203.2019.2.29 Mironov, A.N., Bunatyan, N.D., Vasil’ev, A.N., Verstakova, O.L., Zhuravleva, M.V., Lepahin, V.K., Korobov, N.V., et al. (2012). Guidelines for conducting preclinical studies of drugs. Part one. p. 944. Moscow, Russia: Grief and K 4 Engalycheva, G.N., Syubaev, R.D., Goryachev, D.V. (2019). Quality standards of preclinical pharmacological studies. The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products 9(4): 248-255. 5 10.30895/1991-2919-2019-9-4-248-255 Parlakpinar, H., Tasdemir, S., Polat, A., Bay-Karabulut, A., Vardi, N., Ucar, M., Yanilmaz, M., Kavakli, A., Acet, A. (2006). Protective effect of chelerythrine on gentamicin-induced nephrotoxicity. Cell Biochem Funct. 24(1):41-48. PMid:15584091 6 10.1002/cbf.1182 Gozhenko, A.I., Vladimirova, M.P., Topor, E.A. (2005). Renal dysfunctions in white rats after a single administration of gentamicin. Nephrology. 9(4): 75-79. [in Russian] 7 Hosaka, E.M., Santos, O.F.P., Seguro, A.C., Vattimo, M.F.F. (2004). Effect of cyclooxygenase inhibitors on gentamicin induced nephrotoxicity in rats. Braz J Med Biol Res. 37(7): 979-985. PMid: 15264004 8 10.1590/S0100-879X2004000700006 Durnev, A.D. (2018). Antimutagenesis and antimutagens. Hum Physiol. 44(3): 116-137. [in Russian] 9 10.1134/S0362119718030052 Horisberger, M.A., de Staritzky, K. (1987). A recombinant human interferon-alpha B/D hybrid with a broad host-range. J Gen Virol. 68(Pt 3): 945- 948. PMid:3029315 10 10.1099/0022-1317-68-3-945 Martal, J.L., Chêne, N.M., Huynh, L.P., L’Haridon, R.M., Reinaud, P.B., Guillomot, M.W., Charlier, M.A., Charpigny, S.Y. (1998). IFN-tau: a novel subtype I IFN1. Structural characteristics, non-ubiquitous expression, structure-function relationships, a pregnancy hormonal embryonic signal and crossspecies therapeutic potentialities. Biochimie 80(8- 9): 755-777. 11 10.1016/S0300-9084(99)80029-7 Blankenstein, T., Qin, Z. (2003). The role of IFNgamma in tumor transplantation immunity and inhibition of chemical carcinogenesis. Curr Opin Immunol. 15(2): 148-154. 12 10.1016/S0952-7915(03)00007-4 Makedonov, G.P., Chekova, V.V., Yakubovskaya, E.L., Zasukhina, G.D. (1990). Modification of DNA repair by human interferons. Acta Biol Hung. 41(1- 3): 187-197. 13 Kumari, S., Naik, P., Vishma, B.L., Salian, S.R., Devkar, R.A., Khan, S., Mutalik, S., Kalthur, G., Adiga, S.K. (2016). Mitigating effect of Indian propolis against mitomycin C induced bone marrow toxicity. Cytotechnology 68(5): 1789-1800. PMid:26590833 PMCid:PMC5023552 14 10.1007/s10616-015-9931-4 Sinitsky, M.Y., Kutikhin, A.G., Tsepokina, A.V., Shishkova, D.K., Asanov, M.A., Yuzhalin, A.E., Minina, V.I., Ponasenko, A.V. (2020). Mitomycin C induced genotoxic stress in endothelial cells is associated with differential expression of proinflammatory cytokines. Mutat Res Genet Toxicol Environ Mutagen. 858-860: 503252. PMid:33198933 15 10.1016/j.mrgentox.2020.503252 Hayashi, M. (2016). The micronucleus test-most widely used in vivo genotoxicity test. Genes Environ. 38, 18. PMid:27733885 PMCid:PMC5045625 16 10.1186/s41021-016-0044-x Agarwal, D.K., Chauhan, L.K. (1993). An improved chemical substitute for fetal calf serum for the micronucleus test. Biotech Histochem. 68(4): 187-188. PMid:8218570 17 10.3109/10520299309104695 The European agency for the evaluation of medicinal products, veterinary medicines and inspections (2001). Committee for veterinary medicinal products. Gentamicin summary report. EMEA/ MRL/803/01-FINAL. November 2001. 1-9. https://www.ema.europa.eu/en/documents/mrl-report/gentamicin-summary-report-3-committee-veterinary-medicinal-products_en.pdf 18 El-Ashmawy, I.M., El-Nahas, A.F., Salama, O.M. (2006). Grape seed extract prevents gentamicininduced nephrotoxicity and genotoxicity in bone marrow cells of mice. Basic Clin Pharmacol Toxicol. 99(3): 230-236. PMid:16930296 19 10.1111/j.1742-7843.2006.pto_497.x Velasco-Velázquez, M.A., Maldonado, P.D., Barrera, D., Torres, V., Zentella-Dehesa, A., Pedraza-Chaverrí, J. (2006). Aged garlic extract induces proliferation and ameliorates gentamicin-induced toxicity in LLC-PK1 cells. Phytother Res. 20(1): 76-78. PMid:16397848 20 10.1002/ptr.1780 Martínez-Salgado, C., Eleno, N., Tavares, P., Rodríguez-Barbero, A., García-Criado, J., Bolaños, J.P., López-Novoa, J.M. (2002). Involvement of reactive oxygen species on gentamicin-induced mesangial cell activation. Kidney Int. 62(5): 1682-1692. PMid:12371968 21 10.1046/j.1523-1755.2002.00635.x Bustos, P.S., Deza-Ponzio, R., Páez, P.L., Albesa, I., Cabrera, J.L., Virgolini, M.B., Ortega, M.G. (2016). Protective effect of quercetin in gentamicin-induced oxidative stress in vitro and in vivo in blood cells. Effect on gentamicin antimicrobial activity. Environ Toxicol Pharmacol. 48, 253-264. PMid:27846408 22 10.1016/j.etap.2016.11.004 Kim, J., Lee, Y., Koh, W.S., Kim, C., Choi, I.Y., Kwon, S.C., Lee, G.S., Han, J.Y., Lee, M. (2007). Genotoxicity assessment of HM10620 containing recombinant human interferon-alpha. Drug Chem Toxicol. 30(1): 83-95. PMid:17364866 23 10.1080/01480540601017744 Bidgoli, S.A., Heshmati, M., Keyhan, H., Afshary, A. (2012). Genotoxicity assessment of ecombinant human interferon gamma in human lymphocytes. JAASP 1(2):107-115. 24 Tsoncheva, V.L., Todorova, K.A., Ivanov I.G., Maximova, V.A. (2008). Influence of interferons on the repair of UV-damaged DNA. Z Naturforsch C J Biosci. 63(3-4): 303-307. PMid:18533478 25 10.1515/znc-2008-3-423 Hara, T., Koyama, K., Miyazaki, H., Ohguro, Y., Shimizu, M. (1977). Safety evaluation of KW-1062. I. Acute toxicity in mice, rats and dogs, subacute and chronic toxicity in rats (author’s transl). Jpn J Antibiot. 30(6): 386-407. 26 Steinbach, T.J., Patrick, D.J., Cosenza, M.E. (2019). Toxicologic pathology for non-pathologists. New York: Springer; Humana 27 10.1007/978-1-4939-9777-0 Haitov, R.M., Ataullahanov, R.I., Allenov, S.N., Alyaev, Y.U.G., Balabolkin, I.I., Batkaev, E.A., Batkaeva, N.V., et al. (2014). Immunotherapy: a guide for physicians. Moskow: GEOTAR-Media [in Russian] 28 Selleri, C., Sato, T., Anderson, S., Young, N.S., Maciejewski, J.P. (1995). Interferon-gamma and tumor necrosis factor-alpha suppress both early and late stages of hematopoiesis and induce programmed cell death. J Cell Physiol. 165(3): 538-546. PMid:7593233 29 10.1002/jcp.1041650312 Lin, F., Karwan, M., Saleh, B., Hodge, D.L., Chan, T., Boelte, K.C., Keller, J.R., Young, H.A. (2014). IFN-γ causes aplastic anemia by altering hematopoietic stem/progenitor cell composition and disrupting lineage differentiation. Blood 124(25): 3699-3708. PMid:25342713 PMCid:PMC4263980 30 10.1182/blood-2014-01-549527 Schroder, K., Hertzog, P.J., Ravasi, T., Hume, D.A. (2004). Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 75(2): 163-189. PMid:14525967 31 10.1189/jlb.0603252 Murayama, T., Takahashi, N., Ikoma, N. (1996). Cytotoxicity and characteristics of mitomycin C. Ophthalmic Res. 28(3): 153-159. PMid:8829171 32 10.1159/000267896 Pawlik, T.M., Keyomarsi, K. (2004). Role of cell cycle in mediating sensitivity to radiotherapy. Int J Radiat Oncol Biol Phys. 59(4): 928-942. PMid:15234026 33 10.1016/j.ijrobp.2004.03.005 Fingert, H.J., Chang, J.D., Pardee, A.B. (1986). Cytotoxic, cell cycle, and chromosomal effects of methylxanthines in human tumor cells treated with alkylating agents. Cancer Res. 46(5): 2463-2467. 34 Wang, X.Y., Crowston, J.G., Zoellner, H., Healey, P.R. (2007). Interferon-alpha and interferon-gamma sensitize human tenon fibroblasts to mitomycin-C. Invest Ophthalmol Vis Sci. 48(8): 3655-3661. PMid:17652735 35 10.1167/iovs.06-1121