Differential Enzymatic Reductions Governing the Differential Hypoxia-Selective Cytotoxicities of Phenazine 5,10-Dioxides

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• 作者：Marí ; a Laura Lavaggi ; Mauricio Cabrera ; Mercedes Gonzá ; lez ; Hugo Cerecetto
• 刊名：Chemical Research in Toxicology
• 出版年：2008
• 出版时间：September 15, 2008
• 年：2008
• 卷：21
• 期：9
• 页码：1900-1906
• 全文大小：183K
• 年卷期：v.21,no.9(September 15, 2008)
• ISSN：1520-5010

文摘

Some derivatives of phenazine 5,10-dioxide are selectively toxic to hypoxic cells commonly found in solid tumors. Previous studies of the phenazine 5,10-dioxide mechanism of action indicated that a bioreduction process could be involved in its selective toxicities, maybe as result of its potential HO^•-releasing capability in hypoxia. The major unresolved aspect of the mechanism of phenazine 5,10-dioxides is the identity of the reductase(s) in the cell responsible for activating the drug to its toxic form and metabolites. We have studied the metabolism in both hypoxia and oxia of some selected 2-amino and 2-hydroxyphenazine 5,10-dioxides, 1−5, using rat liver microsomal and cytosol fractions. Differential hypoxic/oxic metabolism was found to be correlated to a compoundʼs cytotoxic selectivity but, in general, without metabolic differences between liver microsomal or cytosolic enzymes. Dicoumarol and ketoconazole were found to inhibit the hypoxic metabolism of the most selective phenazine 5,10-dioxide, 1, inferring a role for DT-diaphorase and cytochrome P450. The least hypoxic selective agents, 4 and 5, possess different hypoxia-metabolic profiles as compared to derivative 1, explaining the differential cytotoxic biological behavior. The nonselective derivative, 2, suffered bioreduction in both conditions and, according to the inhibition studies with dicoumarol and ketoconazole, involves both DT-diaphorase and cytochrome P450. The nontoxic derivative, 3, showed poor bioreductive behavior.