[Polymorphism and the level of P450 gene expression in xenobiotic metabolism]

Polymorphism and the level of P450 gene expression influence metabolic pathway of xenobiotics. The highest number, over 40 polymorphic forms were determined for CYP2D6 enzyme and they expressed various activity. Whereas, only two forms of lower activity were found in the case of CYP2C9. However, CYP3A4 mutations have not influenced metabolic activity of the enzyme. Three transcription factors PXR, CAR and AhR are crucial for gene expression regulation of cytochrome P450. They regulate the induction of CYP3A4, CYP2B6 and CYP1A2 genes, respectively. PXR is activated by binding specific ligand, whereas the activator of constitutive CAR receptor seems not to be the ligand and it might induce dephosphorylation. After being transported to the nucleus, activated receptors PXR, CAR or AhR formed heterodimers and then, with participation of the following coactivators bind to PBREM, XREM or DRE regulatory motifs of DNA, respectively. The activation of nuclear receptors strongly influences the drug-drug interactions that are essential for the efficiency of drug, particularly in the field of anticancer therapy.