PT  - JOURNAL ARTICLE
AU  - Denggao Yao
AU  - Shaohong Ding
AU  - Brian Burchell
AU  - C. Roland Wolf
AU  - Thomas Friedberg
TI  - Detoxication of Vinca Alkaloids by Human P450 CYP3A4-Mediated Metabolism: Implications for the Development of Drug Resistance
DP  - 2000 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 387--395
VI  - 294
IP  - 1
4099  - http://jpet.aspetjournals.org/content/294/1/387.short
4100  - http://jpet.aspetjournals.org/content/294/1/387.full
SO  - J Pharmacol Exp Ther2000 Jul 01; 294
AB  - Vinca alkaloids are important chemotherapeutic agents, and their pharmacokinetic properties display significant interindividual variations, possibly due to CYP3A4-mediated metabolism. We have evaluated the relevance of this metabolism for the chemotherapeutic and the toxicological properties of these drugs. Analysis was performed using Chinese hamster ovary cell lines that expressed either CYP2D6 or CYP3A4. The latter cells metabolized vinblastine with a turnover number of 0.4 min−1, resulting in a decreased cytotoxicity of this compound. Whereas vincristine and vinblastine at a concentration of 100 nM killed more than 90% of the parental cells, more than 50 and 35%, respectively, of cells that coexpressed CYP3A4 and cytochrome P450 (P450) reductase survived these treatments. No additional increase in cytotoxicity was noted above 100 nM. Similarly, preincubation of vinblastine with bacterial membranes that contained recombinant CYP3A4 and P450 reductase decreased the cytotoxicity of vinblastine for parental Chinese hamster ovary cells. We also demonstrate that the presence of vinblastine in a coculture of cells that expressed β-galactosidase together with cells that expressed CYP3A4 strongly selected for the latter cells, resulting in an increased level of CYP3A4 in the surviving cell population. Similarly, treatment of the human colon adenocarcinoma cell line LS174T with vinblastine selected for a cell population with higher levels of endogenous CYP3A4 as revealed by immunohistochemistry without simultaneous increase of multidrug resistance protein 1 (MDR1). This is the first evidence that tumor P450s have the potential to contribute to the development of drug resistance during chemotherapy. The American Society for Pharmacology and Experimental Therapeutics