Genetic polymorphisms and epigenetics changes in human metabolizing enzymes genes to predict differential therapeutic drug effects

Abstract

It has been understood that genetic variability can influence individual ability to metabolize drugs (Kiyohara C. et al., 2002). In particular, sequence changes into some genes give to subject a variable capability to response to a therapy protocol, to begin a resistance toward therapeutic drugs or, on the contrary, to be more sensible to it: the genes of CYP-family, CYP2A6 and CYP2E1, are good examples. Nevertheless, gene expression can be affected either by DNA sequence mutations (polymorphisms) or by “epigenetic modifications”, such as DNA methylation of a CpG islands in a gene promoter ion (Zhu J. et al., 2009). For these reasons, it is indispensable, today, to integrate genetic analyses with epigenetic data, especially with the aim to determine the appropriate personalized therapy in presence of some particular genotypes and specific DNA methylation patterns. Moreover, the obtained data can be used to determine “susceptibility integrated profiles”, very useful in prevention, diagnosis and therapy of some tumors. This project aims to assess, in human cellular lines, the relationship between genetic and epigenetic variations of some genes, the capability to metabolize some drugs as consequence to have those (epi)genotypes and the final effects that treatments do in terms of cytogenetic tests (micronuclei, sister chromatid exchanges, comet assay, etc). Firstly we have to clarify the promoter region of CYP2E1 gene (as a model of other CYP genes) to understand its epigenetic influence in its gene expression. Obtained data can contribute to a personalized therapy, according to more recent and relevant therapeutic criteria.