In-vitro genotoxicity assessment of an anti-diabetic drug using modified media

Abstract

The drug compounds are tested for safety for human use before they enter into the market using various in vitro and in vivo cellular toxicity endpoints including genotoxicity. However, post-marketing reports of safety issues of drugs are not uncommon. The safety analysis is carried out in normal cell culture conditions which is not likely to be good surrogates for the in vivo microenvironment and physiology of patients. The safety analysis in altered culture conditions could be an interesting approach to predict the in vivo toxicity of a drug. In the present study we have used vitamin deficient media to assess genotoxicity of Metformin, a widely used anti-diabetic drug which is linked with vitamin deficiency on a long term use in terms of frequency of chromosome aberrations in lymphocyte cultures. The lymphocyte cultures for metaphase chromosome studies were compared for chromosome aberration frequency using normal media as compared to modified culture media in two different sets of experiments using vitamin B-6, and B-12 deficiency. The deficiency of these vitamins are linked with increased risk of cancer which results from exposure to genotoxic agents. Thus, the higher levels of mean CA/cell values in metaphase cells cultured in vitamin deficient media following exposure to Metformin as compared to normal media suggests that the altered safety outcome of drugs may be due to the altered physiological conditions in patients. The present report demonstrates novel approach for in vitro genotoxicity assessment and can serve as a model for customized adaptations for drug safety relevant to pathophysiological conditions.