Moderate Toxicity of Potential Boron-containing Therapeutic, Dipotassium-trioxohydroxytetrafl uorotriborate -K2(B3O3F4OH) in Rats and Mice
DOI:
https://doi.org/10.1590/s2175-97902023e21384Keywords:
Halogenated boroxine;, BALB/c mice;, Wistar rats;, Sprague-Dawley rats;, drug developmentAbstract
Biological activity of boron-containing compounds (BCCs) has been well-known. Growing interest and numerous applications for BCCs have been reported. Boron and boron-containing acids show low acute toxicity in mammals but data on halogenated boroxine (HB) - dipotassium-trioxohydroxytetrafluorotriborate, K2(B3O3F4OH) acute toxicity have not been reported before. This compound, characterized as a potential therapeutic for skin changes, exhibits no observable genotoxicity in doses lower that 0.1 mg/ml in vitro and 55 mg/kg in vivo. It has also been confirmed as an antitumour agent both in vitro and in vivo as well as an inhibitor of enzymes involved in antioxidant mechanisms. The aim of this study was to assess the acute toxicity of HB and to determine the maximum tolerated dose as well as a dose free of any signs of toxicity in different test organisms. Acute toxicity of HB was tested in Sprague-Dawley and Wistar rats and BALB/c mice after single parenteral application of different doses. We determined doses free of any sign of toxicity and LD50 after single dose administration. LD50 of HB ranges from 63 to 75 mg/kg in different test models, meaning that HB shows moderate toxicity.
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Al Shoyaib A, Archie SR, Karamyan VT. Intraperitoneal Route of Drug Administration: Should it Be Used in Experimental Animal Studies? Pharm Res. 2019;37(1):12.
Animal Welfare Law, Official gazette of Bi&H No. 25/09.
Argyriou AA, Cavaletti G, Bruna J, Kyritsis AP, Kalofonos HP. Bortezomib induced peripheral neurotoxicity: an update. Arch Toxicol. 2014;88(9):1669-1679.
Bakirdere S, Örenay S, Korkmaz M. Effect of Boron on Human Health. Open Miner Process J. 2010;3:54-59.
Ciani L, Ristori S. Boron as a platform for new drug design. Expert Opin Drug Discov. 2012;7(11):1017-1027.
Das BC, Thapa P, Karki R, Schinke C, Das S, Kambhampati S, et al. Boron chemicals in diagnosis and therapeutics. Future Med Chem. 2013;5(6):653-676.
Farfán-García ED, Castillo-Mendieta NT, Ciprés-Flores FJ, Padilla-Martínez II, Trujillo-Ferrara JG, Soriano-Ursúa MA. Current data regarding the structure-toxicity relationship of boron-containing compounds. Toxicol Lett. 2016;258:115-125.
Fu H, Fang H, Sun J, Wang H, Liu A, Sun J, et al. Boronic acid-based enzyme inhibitors: a review of recent progress. Curr Med Chem. 2014;21(28):3271-3280.
Galic B. Boroxine composition for removal of skin changes. Patent No. US 8278289 B2. United States Patent. 2012.
Galic B. Removal of skin changes. Patent No.1996514 B1. European Patent. 2013.
Garabrant DH, Bernstein L, Peters JM, Smith TJ, Wright WE. Respiratory effects of borax dust. Br J Ind Med. 1985;42(12):831-837.
Gochfeld M. Sex Differences in Human and Animal Toxicology. Toxicol Pathol. 2017;45(1):172-189.
Guo Z, Shin I, Yoon J. Recognition and sensing of various species using boronic acid derivatives. Chem Commun. 2012;48(48):5956-5957.
Hadzic M, Haveric S, Haveric A Lojo-Kadric N, Galic B, Ramic J, et al. Bioflavonoids protect cells against halogenated boroxine-induced genotoxic damage by upregulation of hTERT expression. Z Naturforsch C. 2019;74(5-6):124-129.
Hadzic M, Haveric S, Haveric A, Galic B. Inhibitory effects of delphinidin and luteolin on genotoxicity induced by K2[B3O3F4OH] in human lymphocytes in vitro. Biologia. 2015;70(4):553-558.
Hall DG. Boronic acids. New York: Wiley. 2005.
Haveric A, Durmic-Pasic A, Alic A, Mujezinovic I, Smajlovic A, Ostojic J, et al. Biochemical and histomorphological findings in Swiss Wistar rats treated with potential boron-containing therapeutic - K2[B3O3F4OH]. J Trace Elem Med Biol. 2020;5;62:126642.
Haveric S, Hadzic M, Haveric A, Mijanovic M, Hadziselimovic R, Galic B. Genotoxicity Evaluation of Dipotassium Trioxohydroxytetrafluorotriborate, K2[B3O3F4OH], in Human Lymphocyte Cultures and Mice Reticulocytes. Braz Arch Biol Techn. 2016;59:e16160195.
Haveric S, Haveric A, Bajrovic K, Galic B, Maksimovic M. Effects of dipotassium trioxohydroxytetrafluorotriborate (K2[B3O3F4OH]) on genetic material and inhibition of cell division in human cell cultures. Drug Chem Toxicol. 2011;34(3):250-254.
Herenda S, Ostojic J, Haskovic E, Haskovic D, Milos M, Galic B. Electrochemical Investigation of the Influence of K2[B3O3F4OH] on the Activity of Immobilized Superoxide Dismutase. Int J Electrochem Sci. 2018;13(4):3279-3287.
Hubbard SA. Comparative toxicology of borates. Biol Trace Elem Res. 1998;66(1-3):343-357.
Islamovic S, Galic B, Milos M. A study of the inhibition of catalase by dipotassium trioxohydroxytetrafluorotriborate K [B3O3F4OH]. J Enzyme Inhib Med Chem. 2014;29(5):744-48.
Ivankovic S, Stojkovic R, Galic Z, Galic B, Ostojic J, Marasaovic M, et al. In vitro and in vivo antitumor activity of the halogenated boroxine dipotassium trioxohydroxytetrafluorotriborate (K2[B3O3F4OH]). J Enzyme Inhib Med Chem . 2015;30(3):354-359.
Ivankovic S, Stojkovic R, Maksimovic M, Galic B, Milos M. Impact of calcium ion on cytotoxic effect of the boroxine derivative, K2[B3O3F4OH]. J Enzyme Inhib Med Chem . 2016;31(Suppl3):70-74.
Liu X, Guo Q, Zhang Y, Li J, Li R, Wu Y, et al. Intraperitoneal Injection Is Not a Suitable Administration Route for Single-Walled Carbon Nanotubes in Biomedical Applications. Dose Response. 2016;14(4):1559325816681320.
McDonald PC, Winum JY, Supuran CT, Dedhar S. Recent developments in targeting carbonic anhydrase IX for cancer therapeutics. Oncotarget. 2012;3(1):84-97.
Organization for Economic Co-operation and Development. OECD. Acute Oral Toxicity - Acute Toxic Class Method. OECD Guideline for the testing of chemicals. No. 423; 2001.
Organization for Economic Co-operation and Development. OECD. Acute Oral Toxicity - Up-and-Down-Procedure (UDP). OECD Guideline for the testing of chemicals. No. 425; 2008.
Organization for Economic Co-operation and Development. OECD. Guidance document on the recognition, assessment and use of clinical signs as humane endpoints for experimental animals used in safety evaluation (No. 19). Environmental Health and Safety Monograph Series on Testing and Assessment; 2000.
Ostojic J, Herenda S, Galijasevic S, Galic B, Milos M. Inhibition of Horseradish Peroxidase Activity by Boroxine Derivative, Dipotassium-trioxohydroxytetrafluorotriborate K2[B3O3F4OH]. J Chem. 2017; Article ID 8134350.
Paramore A, Frantz S. Bortezomib. Nat Rev Drug Discov. 2003;2(8):611-612.
Pojskic L, Haveric S, Lojo-Kadric N, Hadzic M, Haveric A, Galic Z, et al. Effects of dipotassium-trioxohydroxyt etrafluorotriborate, K2[B3O3F4OH], on cell viability and gene expression of common human cancer drug targets in a melanoma cell line. J Enzyme Inhib Med Chem . 2016;31(6):999-1004.
Renaud HJ, Cui JY, Khan M, Klaassen CD. Tissue distribution and gender-divergent expression of 78 cytochrome P450 mRNAs in mice. Toxicol Sci. 2011;124(2):261-77.
Ryss IG, Slutskaya MM. Report on the platinum sector. Akademii Nauk SSSR. 1951;26:216-218.
Scott H, Walmsley RM. Ames positive boronic acids are not all eukaryotic genotoxins. Mutat Res Genet Toxicol Environ Mutagen. 2015;777:68-72.
Soriano-Ursúa MA, Das BC, Trujillo-Ferrara JG. Boron-containing compounds: Chemico biological properties and expanding medicinal potential in prevention, diagnosis and therapy. Expert Opin Ther Pat. 2014a;24(5):485-500.
Soriano-Ursúa MA, Farfán-García ED, López-Cabrera Y, Querejeta E, Trujillo-Ferrara JG. Boron-containing acids: Preliminary evaluation of acute toxicity and access to the brain determined by Raman scattering spectroscopy. Neurotoxicology. 2014b;40:8-15.
Vullo D, Milos M, Galic B, Scozzafava A, Supuran CT. Dipotassium-trioxohydroxytetrafluorotriborate, K2[B3O3F4OH], is a potent inhibitor of human carbonic anhydrases. J Enzyme Inhib Med Chem . 2015;30(2):341-344.
Wang Y, Ning ZH, Tai HW, Long S, Qin WC, Su LM, et al. Relationship between lethal toxicity in oral administration and injection to mice: effect of exposure routes. Regul Toxicol Pharmacol. 2015;71(2):205-212.
Weber K, Razinger T, Hardisty JF, Mann P, Martel KC, Frische EA, et al. Differences in rat models used in routine toxicity studies. Int J Toxicol. 2011;30(2):162-173.
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