The influence of ascorbic acid on the free-radical metabolism of xenobiotics: the example of diaziquone.

Diaziquone (AZQ) is a quinone-containing alkylating agent undergoing trials as an antitumor drug. The quinone moiety of this compound places it among a group of compounds whose activity is believed to be modulated by a redox cycle that activates the compounds to their free radicals (e.g., adriamycin). AZQ is unique among these compounds in that it can be reduced to its free radical (AZQH) by a variety of cells in culture, including human and murine cancer cells. Red blood cells (RBC) were also observed to reduce AZQ to its free radical. Using electron spin resonance (ESR), we observed that soon after the AZQ free radical appeared, it decayed and was replaced by a doublet with ESR parameters that suggested the presence of the ascorbyl radical (AH). The identity of AH was confirmed by adding exogenous ascorbic acid to AZQ free radicals generated by a suspension of L1210 murine leukemia cells. The endogenous ascorbic acid was shown to arise mostly from the "buffy coat" of an RBC preparation which contained leukocytes. Leukocytes are second only to the adrenals in level of ascorbic acid in humans. Cyclic voltammetry of ascorbic acid, AZQ, and adriamycin in Hank's Balanced Salt Solution (HBSS pH 7.5), the buffer used for biological measurements, showed that the oxidation peak potential for ascorbic acid (Eap = +0.43 V) is closer to the reduction peak potential for AZQ (Ecp = -0.36 V) than that for adriamycin (Ecp = -0.67 V). This may explain why the ascorbic acid redox system interacts with that of AZQ but not with that of ADR.