Aspects of Gene Regulation of CYP3A4 in Hepatic Tissue.

1 Summary CYP3A4 is an important enzyme involved in elimination of majority of metabolized xenobiotics. It plays a major role in the detoxification system of the human body, therefore it is responsible for many drug-drug interactions (DDIs). DDI present a complication of current pharmacotherapy, in the extreme they can lead in failure of therapy or in life-threatening toxic effects. DDIs are caused by changes in enzymatic activity of CYP3A4, which is highly variable among individuals. An important mechanism of modulating CAP3A4 activity is the regulation of inducible transcription by nuclear receptors, especially PXR, CAR and GR. The structure of CYP3A4 promoter and mechanisms of transcriptional regulation has been studding intensively for many years, but the research of relationship of nuclear receptors and transcriptional cofactors in CYP3A4 transactivation is still incomplete. Present work contributes to elucidation of some questions concerning the effects of azole antimycotics on CYP3A4 transcription via PXR, potency of valproic acid to activate PXR and CAR or determinants of CYP3A4 expression via GR in placental cells. The experiments were performed with up-to-date molecular biology methods and using in vitromodels of the primary human hepatocytes and hepatoma cell lines. To the aims of the doctoral..