Value of polymorphisms and DNA methylation for the expression of CYP2E1 enzyme: implications in pharmacogenomics

Risultato della ricerca: Conference contribution

Abstract

Different individuals possess slightly different genetic information and show genetically-determined differencesin several enzyme activities due to genetic variability. Following an integrated approach, we studied thepolymorphisms and DNA methylation of the 5′ flanking region of the metabolizing enzyme CYP2E1 in correlationto its expression in both tumor and non-neoplastic liver cell lines, since to date little is known about theinfluence of these (epi)genetic elements in basal conditions and under induction by the specific inductor and ademethylating agent. In treated cells, reduced DNA methylation, assessed both at genomic and gene level, wasnot consistently associated with the increase of enzyme expression. Interestingly, the Rsa/Pst haplotypedifferentially influenced CYP2E1 enzyme expression. In addition, regarding the Variable Number of TandemRepeats polymorphism, cells with A4/A4 genotype showed a greater expression inhibition (ranging from 20% to30%) compared with others carrying the A2/A2 one, while those cells bringing A2/A3 genotype showed anincrease of expression (of 25%, about). Finally, we demonstrated for the first time that the A2 and A3 CYP2E1alleles play a more important role in the expression of the enzyme, compared with other (epi)genetic factors,since they are binding sites for trans-acting proteins. In conclusion our data contributes to define a hypotheticalmodel of regulation of the expression of this enzyme. Clarifying the complex regulation of CYP2E1 enzymeexpression, either by genetic or epigenetic elements, will give useful topics in pharmacogenomics, for typingpeople regarding its metabolizing capability and therapy response.
Lingua originaleEnglish
Titolo della pubblicazione ospiteAtti delle Giornate Argentine 2014 del Consorzio Interuniversitario Italiano per l'Argentina (CUIA)
Numero di pagine1
Stato di pubblicazionePublished - 2014

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