Effect of glycyrrhizic acid and its derivatives on the
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Poster Presentations 130 EFFECT OF GLYCYRRHIZIC ACID AND ITS DERIVATIVES ON THE VOLUME-REGULATED ANION CHANNEL AND MAXI-Cl CHANNEL D. D. Fayziev 1 , N. А . Tsiferova 1,2 , M. B. Rakhimova 1 , R. S. Kurbannazarova 1 , P. G. Merlyak 1 , R. Z. Sabirov 1,3 1) Institute of Biophysics and Biochemistry NUUz, 2) Center for Advanced Technologies of the Ministry of Innovative Development of RUz, 3) Department of Biophysics, Faculty of Biology NUUz Glycyrrhizin (glycyrrhizic acid, GL) is a triterpene saponin and the major active component of licorice ( Glycyrrhiza glabra ). It is known to exhibit a number of biological activities, such as affecting apoptosis of cancer cells, inhibiting carcinogenesis, enhancing biological effects of other drugs, antiviral. Natural GL has two epimers differing in the orientation of the hydrogen atom at 18 th carbon and termed 18 α - and 18 β -glycyrrhizin. Correspondingly, its aglycone, glycyrrhetic acid (GA), also exists as two isomers: α -GA and β -GA. Hemisuccinate of GA known as carbenoxolone (CBX) was successfully used for treatment of gastric and duodenal ulcers. Although there have been a number of studies on the biological activities of GL and GA, their effect on the volume-regulated anion channel (VRAC) and the Maxi-Cl channel remain unexplored. Experiments were performed using the patch-clamp method on the human colorectal cancer HCT 116 cells. In response to 100 μ M GL, we observed a clear but incomplete suppression of the macroscopic swelling-activated anion current. The effect was fully reversible. The current was suppressed exclusively at positive but not negative potentials indicating that the effect is voltage-dependent. The dose-response curve of the effect of GL on the macroscopic VRAC currents within the concentration range of 0-200 μ M was well fitted by the Hill equation with half-maximum inhibition at 61.9±8.8 μ M and Hill coefficient of 2.2±0.7. In contrast to GL, in similar experiments with α -GA at the same concentration range, no statistically significant effect on the VRAC currents has been revealed. However, β -GA, at a concentration of 50 μ M produced a gradual suppression of the swelling-activated macroscopic current. The effect was fully reversible. The ionic current was suppressed both at positive and negative potentials, which indicates that the effect is voltage-independent. The dose- dependency of the effect of β -GA on VRAC in the concentration range of 0-200 μ M was well fitted with the Hill equation with the concentration of half-maximal effect at 18.4±0.5 μ M and a Hill coefficient of 2.1±0.1. In our further experiments, we investigated the effect of CBX. The results obtained showed that CBX inhibited VRAC in a dose-dependent manner with the concentration of half- maximum effect at 28.6±2.5 μ M and a Hill coefficient of 2.0±0.3. In the next series of experiments, we studied effects of GL and its derivatives on the Maxi- Cl channels in the channel-rich mouse mammary C127 cells. The results showed that neither GL, nor GA in its α - or β -form affected the Maxi-Cl channel activity. Similarly, CBX had no appreciable effect either. It can be concluded that GL is a weak voltage-dependent blocker, whereas β -GA (but not α -GA) as well as CBX are voltage-independent inhibitors of VRAC. The effect is specific for VRAC and is completely absent for the Maxi-Cl channels that also belongs to the volume- activated anion channel superfamily. Document Outline
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