DNA damage induced by reductively activated nitroimidazoles--pH effects.

The effect of pH on E. coli DNA damage measured viscometrically and induced by electrolytically reduced metronidazole and misonidazole has been studied, together with the effect on the statistical average number of electrons required for reduction, measured by high-resolution coulometry, and nitrite production measured colorimetrically. In general, nitroimidazole-induced DNA damage is greatest at acid pH and decreased at alkaline pH, but whereas metronidazole exhibits a linear relationship between DNA damage and increased pH, misonidazole shows a plateau between pH 6 and 8. The electron requirements for complete reduction (n) vary with pH. For misonidazole n increases with an increase in pH both in the absence and presence of DNA with a shallow plateau between pH 6 and 8. In contrast, for metronidazole, n decreases with increased pH and exhibits breakpoints between pH 6 and 8. Nitrite (NO2-) production is linear with increased pH for misonidazole but for metronidazole (NO2-) production shows a sudden increase at 7.5 yielding ca. 35% on a molar basis. The results may reflect differences in the relative stability and reactivity of the nitro radical anion.