engleski

Role of sister chromatid exchange analysis in assessment of proguanil genotoxicity in cultured human lymphocytes

Proguanil hydrochloride is a prodrug of cycloguanil, a dihydrofolate reductase inhibitor, which in malaria parasites Plasmodium falciparum blocks DNA synthesis. In this study, evaluation of DNA damage in human lymphocytes after proguanil treatment in vitro was made by virtue of measuring frequency of sister chromatid exchanges (SCE) as a sensitive biomarker in assessment of DNA integrity since SCE are known to increase as a result of the exposure to various genotoxic agents. Different concentrations of proguanil obtained from the plasma concentrations ; 130 ng/ml for prophylactic treatment and 520 ng/ml for the treatment of malaria were used with and without metabolic activation (S9) in different lenghts of time. SCE technique allows metaphases in first, second and third division to be recognized after culturing. For this reason, the SCE analysis was also employed in estimation of proliferation kinetics after the proguanil treatment. Results of the frequencies of SCE in human lymphocytes did not show statistically significant deviation from the control samples even though mean SCE per cell in all the exposed samples was slightly higher than in corresponding controls and was more prominent with metabolic activation (S9). In addition, the percentage of high frequency cells (HFC) for each sample was estimated using the pooled distribution of all SCE measurements. This parameter also did not show significant deviation compared to the control samples. Results revealed that proguanil did not inhibit lymphocyte proliferation in significant manner, therefore proguanil can be considered relatively safe from the aspect of genotoxicity, especially if used for prophylactic treatment.

Proguanil ; Cycloguanil ; Human lymphocytes ; Genotoxicity ; Comet assay ; Sister chromatid exchange analysis

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