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Titolo:
THE ROLE OF SPECIFIC REDUCTASES IN THE INTRACELLULAR ACTIVATION AND BINDING OF 2-NITROIMIDAZOLES
Autore:
JOSEPH P; JAISWAL AK; STOBBE CC; CHAPMAN JD;
Indirizzi:
FOX CHASE CANC CTR,DEPT PHARMACOL,7701 BURHOLME AVE PHILADELPHIA PA 19111 FOX CHASE CANC CTR,DEPT RADIAT ONCOL PHILADELPHIA PA 19111
Titolo Testata:
International journal of radiation oncology, biology, physics
fascicolo: 2, volume: 29, anno: 1994,
pagine: 351 - 355
SICI:
0360-3016(1994)29:2<351:TROSRI>2.0.ZU;2-I
Fonte:
ISI
Lingua:
ENG
Soggetto:
HYPOXIC MAMMALIAN-CELLS; SELECTIVE CHEMOTHERAPY; MISONIDAZOLE; INVITRO; NITROIMIDAZOLE; REDUCTION; TISSUES; TUMORS; MOUSE;
Keywords:
2-NITROIMIDAZOLE; P450 REDUCTASE; DT-DIAPHORASE; HYPOXIC MARKERS; NITROREDUCTASES;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
25
Recensione:
Indirizzi per estratti:
Citazione:
P. Joseph et al., "THE ROLE OF SPECIFIC REDUCTASES IN THE INTRACELLULAR ACTIVATION AND BINDING OF 2-NITROIMIDAZOLES", International journal of radiation oncology, biology, physics, 29(2), 1994, pp. 351-355

Abstract

Purpose: To determine the relative effectiveness of specific cellularreductases for the activation and binding of 2-nitroimadazoles in vivo. Methods and Materials: Monkey kidney cells were transfected with recombinant plasmids to effect intracellular overexpression of P450 reductase and DT-diaphorase. The covalent binding of 2-nitroimidazoles to cellular macromolecules was measured as a function of time of cell incubation at various oxygen concentrations. The effect of allipurinol oncellular binding of radiolabeled 2-nitroimidazoles was also measured. Results: A 1,000-fold overexpression of DT-diaphorase resulted in a small but significant increase in 2-nitroimidazole binding rate. An 80-fold overexpression of cytochrome P450 reductase resulted in a 5-7-fold increase in the binding rate of 2-nitroimidazole. The inhibition of xanthine oxidase by allipurinol had no effect on 2-nitroimidazole binding rates. The amplification of P450 reductase activity within cells was always much larger than the resultant increase in 2-nitroimidazole binding rate, suggesting an enzyme kinetic process less than first order and possibly of 1/2-order. Conclusion: These data suggest that cytochrome P450 reductase is the most important enzyme in these cells for reducing 2-nitroimidazoles to intermediates which can covalently bind to cellular macromolecules. Furthermore, since this cellular process demonstrates similar to 1/2-order kinetics, a tissue's capacity for binding 2-nitroimidazole drug in hypoxia should be proportional to the square root of its intracellular P450 reductase level.

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Documento generato il 07/07/20 alle ore 05:51:32