The impact of DNA methylation on the expression of CYP3A4 gene

Abstract

Epigenetic alterations involved in the expression of drug-metabolizing enzyme genes make a significant contribution to interindividual differences in drug response. Pharmacoepigenetic research has the potential to improve patient care by predicting adverse drug reactions. One of the most common epigenetic modifications is DNA methylation, which can occur in genes encoding drug-metabolizing enzymes and can affect the pharmacokinetics of drugs. The mechanisms of DNA methylation are likely to influence the interindividual expression of CYP3A4. This study aims to investigate the epigenetic factors altering the regulation of CYP3A4 enzyme activity in chronic kidney disease (CKD). The gene expression profiles of CYP3A4 and the nuclear receptor PXR genes were evaluated in patients with CKD (n=67) and healthy controls (n=29) by RT-PCR analysis. The differentially methylated CpG promoter region of the CYP3A4 gene was analyzed by bisulfite sequencing. The expression levels of CYP3A4 and PXR genes were found low in CKD patients (1.92±0.22 and 0.87±0.07, respectively) when compared to healthy controls (2.54±1.08 and 1.42±0.25, respectively) and the association was found significant for PXR (p<0.05). The demethylation rates of the CYP3A4 promoter were associated with glomerular filtration rates (p<0.05). This study revealed the importance of analyzing DNA methylation profiles of genes involved in drug metabolism to predict adverse effects in patients with chronic kidney disease who are exposed to polypharmacy. Further studies in this area are promising for the development of new biomarkers.