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It has been suggested that taurine, hypotaurine and their metabolic precursors (cysteic acid, cysteamine and cysteinesulphinic acid) might act as antioxidants in vivo. The rates of their reactions with the biologically important oxidants hydroxyl radical (.OH), superoxide radical (O2.-), hydrogen peroxide (H2O2) and hypochlorous acid (HOCl) were studied. Their ability to inhibit iron-ion-dependent formation of .OH from H2O2 by chelating iron ions was also tested. Taurine does not react rapidly with O2.-, H2O2 or .OH, and the product of its reaction with HOCl is still sufficiently oxidizing to inactivate alpha 1-antiproteinase. Thus it seems unlikely that taurine functions as an antioxidant in vivo. Cysteic acid is also poorly reactive to the above oxidizing species. By contrast, hypotaurine is an excellent scavenger of .OH and HOCl and can interfere with iron-ion-dependent formation of .OH, although no reaction with O2.- or H2O2 could be detected within the limits of our assay techniques. Cysteamine is an excellent scavenger of .OH and HOCl; it also reacts with H2O2, but no reaction with O2.- could be measured within the limits of our assay techniques. It is concluded that cysteamine and hypotaurine are far more likely to act as antioxidants in vivo than is taurine, provided that they are present in sufficient concentration at sites of oxidant generation.

Mitomycin C, an antitumor antibiotic, is known to require reductive activation in order to function as an alkylating agent. In this work reduction has been carried out by using radiolytically produced formate radicals that reduce mitomycin C to its semiquinone in a clean rapid one-electron reaction. The ultimate products of the reduction are cis- and trans-2,7-diamino-1-hydroxymitosene (B1 and B2) and 2,7-diaminomitosene (C). The yields of these compounds were found to be the same when the rate of reduction was varied by 11 orders of magnitude. At pH 7, one mitosene molecule is formed for every two formate radicals, while at pH 9.1, about eight mitosene molecules are formed per formate radical. The ratio of (B1 + B2)/C is less than 0.4 at pH 5.7, 1.0 at pH 7, and greater than 3.5 at pH 9.1. Observations have been made of changes in optical absorption due to the formation of the semiquinone and hydroquinone of both mitomycin C itself and 2,7-diamino-1-hydroxymitosene (B). The direct conversion of the semiquinone form of mitomycin C into the semiquinone of B proceeds slowly, if at all. The semiquinone form of B will rapidly reduce mitomycin C (k = 7.2 X 10(8) M-1 s-1). The hydroquinone of mitomycin C undergoes changes resulting in the formation of B and C. The yields of B and C depend on pH.(ABSTRACT TRUNCATED AT 250 WORDS)

Several bifunctional alkylating agents of the aziridinylbenzoquinone class have been evaluated as potential antitumor agents. 3,6-Bis[(2-hydroxyethyl)amino]-2,5- diaziridinyl-1,4-benzoquinone (BZQ), 2,5-diaziridinyl-1,4-benzoquinone (DZQ), 3,6-bis(carboxyamino)-2,5-diaziridinyl- 1,4-benzoquinone (AZQ), and six analogues of AZQ have been studied for their ability to induce DNA interstrand cross-linking, as measured by an agarose gel technique, and to determine whether they react with DNA in a sequence-selective manner, as determined by a modified DNA sequencing technique. At an equimolar concentration (10 microM), only DZQ and BZQ showed any detectable cross-linking at pH 7 without reduction. Cross-linking was enhanced in both cases at low pH (4). Reduction by ascorbic acid at both pH's increased the cross-linking, which was particularly striking in the case of DZQ. In contrast, AZQ and its analogues only produced a significant level of cross-linking under both low-pH and reducing conditions, the extent of cross-linking decreasing as the size of the alkyl end group increased. The compounds reacted with all guanine-N7 positions in DNA with a sequence selectivity similar to other chemotherapeutic alkylating agents, such as the nitrogen mustards, although some small differences were observed with BZQ. Nonreduced DZQ showed a qualitatively similar pattern of reactivity to the other compounds, but on reduction (at pH 4 or 7) was found to react almost exclusively with 5'-GC-3' sequences, and in particular, at 5'-TGC-3' sites. A model to explain this unique reaction is proposed.

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