Threshold for antiproliferative and proapoptotic activity of ttaxol in HepG2 cells expressing human CYP3A4: effect of P-glycoprotein transporters.

Taxol treatment froze the cell cycle in the G(2)/M phase, induced morphological changes characteristic of apoptotic/necrotic cell death and increased CYP3A4 enzymatic activity, CYP3A4 mRNA and protein levels in HepG2 cells overexpressing CYP3A4. Apoptosis was associated with cytochrome c release to the cytosol; however, at higher Taxol levels, cells became relatively resistant to the drug-induced freezing of the cell cycle and saturation thresholds for both antiproliferative and proapoptotic activity of Taxol were observed. P-Glycoprotein expression was only slightly increased by Taxol, however, P-glycoprotein-mediated pumping efficiency was significantly increased. Preincubation of cells with an anti-MDR1 monoclonal antibody prior to the drug treatment, coincubation of cells with a potent CYP3A4 inhibitor--ketoconazole--or with both compounds increased Taxol toxicity and proapoptotic activity, indicating that the P-glycoprotein system has a major role in Taxol disposition in hepatoblastoma cells.