Metabolic pathways of drugs and other xenobiotics are strongly influenced in human organism by the polymorphism of cytochrome P450 and other phase I and phase II enzymes as well as by the level of their gene expression. The highest number of P450 isoenzymes, of various activity, over 40 polymorphic forms, were determined for CYP2D6 isoenzyme. Only two forms of lower activity were found in the case of CYP2C9, whereas CYP3A4 mutations have not influenced metabolic activity of the enzyme. Three transcription factors PXR, CAR and AhR participate in the expression regulation of P450 genes, CYP3A4, CYP2B6 and CYP1A2, respectively. Receptors PXR, CAR and AhR are transported to the nucleus, and activated to heterodimers. Then, after following coactivation heterodimers bind to PBREM, XREM or DRE regulatory motifs of DNA, respectively.

A variety of drugs, including antitumor agents, were found to modulate the level P450 gene expression by interaction with PXR or CAR receptors, what is a source of drug-drug interactions. Molecular mechanisms of these interactions are still not known in details. However, there were demonstrated that antitumor drug paclitaxel but not docetaxel is an agonist of PXR. Tamoxifen, being the antagonist of the estrogen receptor binds similarly as an estradiol, while cyclophosphamide used together with PXR and CAR agonists rifampicyne and phenobarbital, is metabolized very fast to toxic metabolites.

In our studies we intended to elucidate whether two antitumor agents 1-nitroacridine and triazoloacridinone derivatives affect the level, gene expression and enzymatic activity of CYP3A4 isoenzyme in HepG2 cancer cells. Western blot analysis, RT-PCR procedure and HPLC control of the reaction pathways were applied. The preliminary results indicated that the studied compounds influenced the action of CYP3A4 in the specific manner. The character of this influence seemed to corroborate with the differences in their metabolic pathways studied earlier.

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1. Glucuronidation of antitumor agents - detoxification, mechanism of drug resistance or the prodrug design? Studies on acridine antitumor agents in the light of clinical therapeutics
2. Metabolism of antitumor 9-amino-1-nitroacridine derivative C-1748 (Capridine-beta) in human hepatoma HepG2 cells
3. Specific metabolism of antitumor agents with cytochrome P-450 isoenzymes
4. The role of hepatic cytochrome P-450 enzymes in metabolism of imidazoacridinone antitumor agent, C1311 (Symadex^R): studies with the hepatic NADPH:cytochrome P450 reductase null mice
5. Metabolic transformations of antitumor agents with cytochrome P-450 isoenzymes
6. Imidazoacridinone antitumor agent, C-1311, as a selective mechanism-based inactivator of human recombinant cytochrome P450 1A2.
7. The role of Cytochrome P450 Reductase in metabolism of potent nitroacridine antitumor agent, C‑1748.
8. METABOLIC TRANSFORMATIONS OF ANTITUMOR AGENTS WITH CYTOCHROME P-450 ISOENZYMES.