In vitro cytogenotoxic evaluation of sertraline

Abstract

Sertraline (SRT) is an antidepressant agent used as a neuronal selective serotonin-reuptake inhibitor (SSRI). SRT blocks serotonin reuptake and increases serotonin stimulation of somatodendritic serotonin 1A receptor (5-HT1AR) and terminal autoreceptors in the brain. In the present study, the genotoxic potential of SRT was evaluated using cytokinesis-block micronucleus (CBMN) cytome assay in peripheral blood lymphocytes of healthy human subjects. DNA cleavage-protective effects of SRT were analyzed on plasmid pBR322. In addition, biochemical parameters of total oxidant status (TOS) and total antioxidant status (TAS) in blood plasma were measured to quantitate oxidative stress. Human peripheral blood lymphocytes were exposed to four different concentrations (1.25, 2.5, 3.75 and 5 μg/mL) of SRT for 24- or 48-h treatment periods. In this study, SRT was not found to induce MN formation either in 24- or 48-h treatment periods. In contrast, SRT concentration-dependently decreased the percentage of MN and MNBN (r=-0.979, p<0.01; r=-0.930, p<0.05, respectively) when it was present for the last 48 hr (48-h treatment) of the culture period. SRT neither demonstrated a cleavage activity on plasmid DNA nor conferred DNA protection against H₂O₂. The application of various concentrations of SRT significantly increased the TOS and oxidative stress index (OSI) in human peripheral blood lymphocytes for both the 24- and 48-h treatment periods. Morover, the increase in TOS was potent as the positive control MMC at both treatment times. However, SRT did not alter the TAS levels in either 24- or 48-h treatment periods when compared to control. In addition, exposing cells to SRT caused significant decreases in the nuclear division index at 1.25, 2.50 and 3.75 μg/mL in the 24-h and at the highest concentration (5 μg/mL) in the 48-h treatment periods. Our results suggest that SRT may have cytotoxic effect via oxidative stress on cultured human peripheral blood lymphocytes.

Keywords: cytotoxicity; micronucleus; oxidative stress; pBR322; peripheral blood lymphocytes; sertraline.

Figure 1

Chemical structure of sertraline.

Figure 2

Regression line and correlation coefficient depicting concentration-dependent reduction of MN in human peripheral blood lymphocytes treated with sertraline for 48 h at different concentrations. *p<0.01

Figure 3

Regression line and correlation coefficient depicting concentration-dependent reduction of MNBN in human peripheral blood lymphocytes treated with sertraline for 48 h at different concentrations. *p<0.05

Figure 4

Agarose gel electrophoresis cleavage pattern of pBR322 plasmid DNA after treatment with SRT in presence of H₂O₂ (lanes: 3, 4, 5, 6) for 5 min. Lane 1: DNA control (H₂O); Lane 3: 1.25 μg/mL SRT+H₂O+DNA; Lane 4: 2.50 μg/mL SRT+H₂O+DNA; Lane 5: 3.75 μg/mL SRT+H₂O+DNA; Lane 6: 5 μg/mL SRT+H₂O+DNA

Figure 5

Agarose gel electrophoresis cleavage pattern of pBR322 plasmid DNA after treatment with SRT alone (lanes: 3, 4, 5, 6) for 5 min. Lane 1: DNA control (H₂O); Lane 2: DNA+H₂O₂+dH2O; Lane 3: 1.25 μg/mL SRT+H₂O₂+DNA; Lane 4: 2.50 μg/mL SRT+H₂O₂+DNA; Lane 5: 3.75 μg/inL SRT+H₂O₂+DNA; Lane 6: 5 μg/mL SRT+H₂O₂+DNA.