Abstract
Glibenclamide is an oral hypoglycemic drug commonly prescribed for the treatment of type 2 diabetes mellitus, whose anti-tumor activity has been recently described in several human cancer cells. The mutagenic potential of such an antidiabetic drug and its recombinogenic activity in eukaryotic cells were evaluated, the latter for the first time. The mutagenic potential of glibenclamide in therapeutically plasma (0.6 μM) and higher concentrations (10 μM, 100 μM, 240 μM and 480 μM) was assessed by the in vitro mammalian cell micronucleus test in human lymphocytes. Since the loss of heterozygosity arising from allelic recombination is an important biologically significant consequence of oxidative damage, the glibenclamide recombinogenic activity at 1 μM, 10 μM and 100 μM concentrations was evaluated by the in vivo homozygotization assay. Glibenclamide failed to alter the frequency of micronuclei between 0.6 μM and 480 μM concentrations and the cytokinesis block proliferation index between 0.6 μM and 240 μM concentrations. On the other hand, glibenclamide changed the cell-proliferation kinetics when used at 480 μM. In the homozygotization assay, the homozygotization indices for the analyzed markers were lower than 2.0 and demonstrated the lack of recombinogenic activity of glibenclamide. Data in the current study demonstrate that glibenclamide, in current experimental conditions, is devoid of significant genotoxic effects. This fact encourages further investigations on the use of this antidiabetic agent as a chemotherapeutic drug.
Highlights
Sulphonylurea is a class of oral antidiabetic agents with long clinical use in patients with type 2 diabetes
Since the analysis of mitotic index (MI) was used as an indicator of glibenclamide cytotoxicity, the glibenclamide concentrations selected for MNvit test were 0.6 μM, 10 μM, 100 μM, 240 μM and 480 μM which produced cytostasis ranging approximately between 6% and 35.75% when compared to that of the negative control (Fig. 5)
Whereas micronucleated cells were rare in glibenclamide-treated cells as well as in untreated cells, mitomycin-C, the positive control, at 0.3 μM concentration, caused a significant rise (p < 0.05) in the number of micronuclei when compared to the negative control
Summary
Sulphonylurea is a class of oral antidiabetic agents with long clinical use in patients with type 2 diabetes These agents are insulin secretagogues which act directly on the pancreatic β cell ATP-sensitive potassium channels (KATP channels) and augment its closure by glucose [1]. A drug used for angina pectoris, activates the KATP channels, the sulphonylureas, e.g., glibenclamide, used to control type 2 diabetes, inhibit the KATP channels by their interaction with the SUR subunit. This inhibition leads to β cell membrane depolarization which results in the opening of voltage-gated Ca2+ channels and in the induction of Ca2+ transport from the extracellular compartment into the cytoplasm of the β cell. A rise in the cytosolic calcium ion concentration linearly increases the exocytosis of the insulin-containing granules into the plasma compartment [1,2,3]
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