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Evaluation of DNA damage in spinal cord and mutagenic effect of a Phα1β recombinant toxin with analgesic properties from the Phoneutria nigriventer spider.
Basic Clin Pharmacol Toxicol. 2019 May; 124(5):615-620.BC

Abstract

Phα1β peptide isolated from the venom of the Phoneutria nigriventer spider has shown higher analgesic action in pre-clinical studies than ω-conotoxin MVIIA peptide used to treat severe chronic pain. In view of the great potential for the development of a new Phα1β-based drug, a Phα1β recombinant form (CTK 01512-2) has been studied for efficacy and safety. The aim of this study was to evaluate cytotoxic, genotoxic and mutagenic effects of a Phα1β recombinant form and compare it with native Phα1β and ω-conotoxin MVIIA. Cytotoxicity was evaluated using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) colourimetric assay in L929 mouse fibroblast cells (0.5-10.0 μmol/L). Genotoxic and mutagenic activities were analysed using the alkaline comet assay in peripheral blood and spinal cord, and the micronucleus test in bone marrow from Wistar rats treated by intrathecal injection of CTK 01512-2 (200, 500 and 1000 pmol/site), native Phα1β (500 pmol/site) and ω-conotoxin MVIIA (200 pmol/site). CTK 01512-2 decreased the cell viability of the L929, showing IC50 of 3.3 ± 0.1 µmol/L, while the Phα1β and ω-conotoxin MVIIA did not show cytotoxicity (IC50 > 5.0 µmol/L). Native and recombinant Phα1β forms induced DNA damage in the spinal cord, but not in peripheral blood. CTK 01512-2 at 1000 pmol/site increased the micronucleus frequency suggesting mutagenic effects. In conclusion, the recombinant form has cytotoxic, genotoxic and mutagenic effects, evidenced in doses five times above the therapeutic dose.

Authors+Show Affiliations

Laboratory of Pharmacology and Toxicology, Lutheran University of Brazil (ULBRA), Canoas, Brazil.Laboratory of Pharmacology and Toxicology, Lutheran University of Brazil (ULBRA), Canoas, Brazil.Laboratory of Pharmacology and Toxicology, Lutheran University of Brazil (ULBRA), Canoas, Brazil. Laboratory of Toxicological Genetics, Lutheran University of Brazil (ULBRA), Canoas, Brazil.Laboratory of Toxicological Genetics, Lutheran University of Brazil (ULBRA), Canoas, Brazil.Laboratory of Pharmacology and Toxicology, Lutheran University of Brazil (ULBRA), Canoas, Brazil. Laboratory of Toxicological Genetics, Lutheran University of Brazil (ULBRA), Canoas, Brazil.Laboratory of Cancer Biology, Lutheran University of Brazil (ULBRA), Canoas, Brazil.Laboratory of Cancer Biology, Lutheran University of Brazil (ULBRA), Canoas, Brazil.Department of Pharmacosciences. Federal, University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, Brazil.Laboratory of Toxins, Institute of Education and Research Santa Casa Belo Horizonte, Belo Horizonte, Brazil.Laboratory of Toxicological Genetics, Lutheran University of Brazil (ULBRA), Canoas, Brazil.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30449066

Citation

de Souza, Alessandra Hubner, et al. "Evaluation of DNA Damage in Spinal Cord and Mutagenic Effect of a Phα1β Recombinant Toxin With Analgesic Properties From the Phoneutria Nigriventer Spider." Basic & Clinical Pharmacology & Toxicology, vol. 124, no. 5, 2019, pp. 615-620.
de Souza AH, da Rosa LG, Uliano MR, et al. Evaluation of DNA damage in spinal cord and mutagenic effect of a Phα1β recombinant toxin with analgesic properties from the Phoneutria nigriventer spider. Basic Clin Pharmacol Toxicol. 2019;124(5):615-620.
de Souza, A. H., da Rosa, L. G., Uliano, M. R., da Silva Prado, L., Ferraz, A. G., Conter, L. U., Grivicich, I., Dallegrave, E., Gomez, M. V., & Picada, J. N. (2019). Evaluation of DNA damage in spinal cord and mutagenic effect of a Phα1β recombinant toxin with analgesic properties from the Phoneutria nigriventer spider. Basic & Clinical Pharmacology & Toxicology, 124(5), 615-620. https://doi.org/10.1111/bcpt.13171
de Souza AH, et al. Evaluation of DNA Damage in Spinal Cord and Mutagenic Effect of a Phα1β Recombinant Toxin With Analgesic Properties From the Phoneutria Nigriventer Spider. Basic Clin Pharmacol Toxicol. 2019;124(5):615-620. PubMed PMID: 30449066.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evaluation of DNA damage in spinal cord and mutagenic effect of a Phα1β recombinant toxin with analgesic properties from the Phoneutria nigriventer spider. AU - de Souza,Alessandra Hubner, AU - da Rosa,Luiza Gabriela, AU - Uliano,Michel Rossi, AU - da Silva Prado,Lismare, AU - Ferraz,Alice Gomes, AU - Conter,Lucas Umpierre, AU - Grivicich,Ivana, AU - Dallegrave,Eliane, AU - Gomez,Marcus Vinícius, AU - Picada,Jaqueline Nascimento, Y1 - 2018/12/13/ PY - 2018/08/24/received PY - 2018/11/06/accepted PY - 2018/11/19/pubmed PY - 2019/9/21/medline PY - 2018/11/19/entrez KW - DNA damage KW - Phα1β KW - comet assay KW - cytotoxicity KW - micronucleus KW - toxins SP - 615 EP - 620 JF - Basic & clinical pharmacology & toxicology JO - Basic Clin Pharmacol Toxicol VL - 124 IS - 5 N2 - Phα1β peptide isolated from the venom of the Phoneutria nigriventer spider has shown higher analgesic action in pre-clinical studies than ω-conotoxin MVIIA peptide used to treat severe chronic pain. In view of the great potential for the development of a new Phα1β-based drug, a Phα1β recombinant form (CTK 01512-2) has been studied for efficacy and safety. The aim of this study was to evaluate cytotoxic, genotoxic and mutagenic effects of a Phα1β recombinant form and compare it with native Phα1β and ω-conotoxin MVIIA. Cytotoxicity was evaluated using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) colourimetric assay in L929 mouse fibroblast cells (0.5-10.0 μmol/L). Genotoxic and mutagenic activities were analysed using the alkaline comet assay in peripheral blood and spinal cord, and the micronucleus test in bone marrow from Wistar rats treated by intrathecal injection of CTK 01512-2 (200, 500 and 1000 pmol/site), native Phα1β (500 pmol/site) and ω-conotoxin MVIIA (200 pmol/site). CTK 01512-2 decreased the cell viability of the L929, showing IC50 of 3.3 ± 0.1 µmol/L, while the Phα1β and ω-conotoxin MVIIA did not show cytotoxicity (IC50 > 5.0 µmol/L). Native and recombinant Phα1β forms induced DNA damage in the spinal cord, but not in peripheral blood. CTK 01512-2 at 1000 pmol/site increased the micronucleus frequency suggesting mutagenic effects. In conclusion, the recombinant form has cytotoxic, genotoxic and mutagenic effects, evidenced in doses five times above the therapeutic dose. SN - 1742-7843 UR - https://www.unboundmedicine.com/medline/citation/30449066/Evaluation_of_DNA_damage_in_spinal_cord_and_mutagenic_effect_of_a_Phα1β_recombinant_toxin_with_analgesic_properties_from_the_Phoneutria_nigriventer_spider_ L2 - https://doi.org/10.1111/bcpt.13171 DB - PRIME DP - Unbound Medicine ER -