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.
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018197:Hepatoblastoma; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D009336:Necrosis; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D002352:Carrier Proteins; D065607:Cytochrome P-450 Enzyme Inhibitors; D012333:RNA, Messenger; D045304:Cytochromes c; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017239:Paclitaxel; D007654:Ketoconazole