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Titolo:
Detoxication of vinca alkaloids by human P450CYP3A4-mediated metabolism: Implications for the development of drug resistance
Autore:
Yao, DG; Ding, SH; Burchell, B; Wolf, CR; Friedberg, T;
Indirizzi:
Univ Dundee, Ninewells Hosp & Med Sch, Biomed Res Ctr, Dundee DD1 9SY, Scotland Univ Dundee Dundee Scotland DD1 9SY ed Res Ctr, Dundee DD1 9SY, Scotland Univ Dundee, Ninewells Hosp & Med Sch, Imperial Canc Res Fund, Mol Pharmacol Unit, Dundee DD1 9SY, Scotland Univ Dundee Dundee Scotland DD1 9SY macol Unit, Dundee DD1 9SY, Scotland Univ Dundee, Ninewells Hosp & Med Sch, Dept Cellular & Mol Pathol, Dundee DD1 9SY, Scotland Univ Dundee Dundee Scotland DD1 9SY Mol Pathol, Dundee DD1 9SY, Scotland
Titolo Testata:
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
fascicolo: 1, volume: 294, anno: 2000,
pagine: 387 - 395
SICI:
0022-3565(200007)294:1<387:DOVABH>2.0.ZU;2-R
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN CYTOCHROME-P450 3A4; HUMAN LIVER-MICROSOMES; ESCHERICHIA-COLI; HUMAN HEPATOCYTES; P450 REDUCTASE; MULTIDRUG-RESISTANCE; MAMMALIAN-CELLS; RAT HEPATOCYTES; P-GLYCOPROTEIN; CHO CELLS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
39
Recensione:
Indirizzi per estratti:
Indirizzo: Friedberg, T Univ Dundee, Ninewells Hosp & Med Sch, Biomed Res Ctr, DundeeDD1 9SY, Scotland Univ Dundee Dundee Scotland DD1 9SY undee DD1 9SY, Scotland
Citazione:
D.G. Yao et al., "Detoxication of vinca alkaloids by human P450CYP3A4-mediated metabolism: Implications for the development of drug resistance", J PHARM EXP, 294(1), 2000, pp. 387-395

Abstract

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 ofcells that expressed beta-galactosidase together with cells that expressedCYP3A4 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 fora 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 25/01/20 alle ore 03:21:43