THE MUTAGENIC PROPERTIES OF THE DRUG BASED ON THE TRIDECAPEPTIDE IN THE AMES TEST AND IN THE MOUSE BLOOD ERYTHROCYTE MICRONUCLEUS TEST

DOI: https://doi.org/10.29296/25877313-2018-08-06
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Issue: 
8
Year: 
2018

A.H. Sharaf Toxicologist, the Group of General and Specific Types of Toxicity, Institute of Experimental Pharmacology (Saint-Petersburg) E-mail: sharaf.ah@doclinika.ru E.D. Bondareva Head of the Biosafety Group, Institute of Experimental Pharmacology (Saint-Petersburg) K.L. Kryshen Ph.D.(Biol.), Head of the Department of Toxicology and Microbiology, Institute of Experimental Pharmacology (Saint-Petersburg) O.N. Pozharitskaja Ph.D.(Pharm.), Deputy Director for New Technologies, Institute of Experimental Pharmacology (Saint-Petersburg) M.N. Makarova Dr.Sc. (Med.), Deputy Director for Science, Institute of Experimental Pharmacology (Saint-Petersburg)

The mutagenic activity of the drug based on the tridecapeptide H-Tyr-D-Arg-Phe-Gly-(D-Arg)8-Gly-OH * 10HCl was studied. The tridecapeptide is a combination of the tetrapeptide (Tyr-D-Arg-Phe-Gly-NH2) and an oligoarginine vector. The introduction of the octoarginine fragment into the structure of the tetrapeptide molecule makes it possible to increase the resistance of the peptide to proteolytic enzymes of the gastrointestinal tract, creating a per-spective of the oral administration of the drug candidate. In addition, for the octoarginine peptides, the ability to penetrate the cell through the membrane through various molecular mechanisms and to increase the permeability of the blood-brain barrier (BBB) has been established. Mutagenic properties have been studied in the mouse blood erythrocyte micronucleus test and in the Ames test. In the Ames test, it was found that the test object at concentrations of 10000.01 μg/ml had no mutagenic effect on the Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 when tested with and without metabolic activation. However, a statistically significant decrease in the number of colonies was revealed, up to their complete absence at the concentration of the investigated substance of 1000 μg/ml, which indicates the cytotoxic effect of the substance H-TYR-D-ARG-PHE-GLY-(D-ARG)8-GLY-OH * 10HCL, which could not be detected in a screening study. A metabolic activation sharply re-duces the cytotoxic properties of the test substance (in a variant of the test with metabolic activation, cytotoxic properties appear only on strain TA98). This suggests that the test object is subjected to methabolism in the liver tissue, which requires further study. The micronucleus test shows the absence of a mutagenic effect of the tridecapeptide substance in doses of 1 mg/kg and 10 mg/kg for single and seven-day intragastric administration.

Keywords: 
mutagenicity
analgesic
tridecapeptide
oligoarginine vector
genotoxicity
micronucleus test
Ames test
cytotoxicity

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