A bacterial mutagenicity study of rivanol, an acridine derivative used as an abortifacient

Abstract

We have used the forward mutation to resistance to 6 azauracil to test the mutagenicity of rivanol (6,9 diamino 2-ethoxy acridine) on Escherichia coli. Rivanol has been used to induce therapeutic abortions in midpregnancy and is considered safe and effective for this purpose. The findings reported here that rivanol, like other acridines, is a mutagen, at least in procaryotes, suggests that such use of rivanol be reconsidered in light of its possible genetic toxicity.

PIP: Rivanol (6, 9 diamino 2-ethoxy acridine) is used in Asia and Sweden as a mid-trimester abortifacient. Although its apparent safety and lack of side effects have been documented in a series of studies, the longterm effects of this agent have not been evaluated. Acridine compounds are known to bind strongly to DNA and to produce mutations, thus it is appropriate to consider the potential of rivanol to lead to genetic damage or cancer. This study used the forward mutation to resistance to 6 azauracil to test the mutagenicity of rivanol and a related known mutagen, acridine orange, on Escherichia coli. Several generations of E. coli cells were grown in the presence of these 2 agents, and the frequencies of cells with the mutant phenotype (upp) among viable cells in the population were determined. Data from 4 independent experiments were averaged. In all experiments, the rivonal-treated sample had fewer viable cells per ml than untreated controls, but this toxicity was not observed for acridine orange. At concentrations or= 100 mcg/ml, acridine orange did not increase the frequency of upp mutants. However, rivanol exhibited a dose-dependent increase in mutation frequency up to 8-fold at 100 mcg/ml. The selective bacterial toxicity observed in the comparison of these 2 agents is attributed to the fact that rivanol binds 2-5 times more strongly to DNA than acridine orange. The low blood levels of rivanol that have been observed after oral and extraamniotic application may be below the concentration that can cause significant genetic damage or induce malignancies. However, it is possible that mammalian cells are more permeable to rivanol than bacterial cells and that low concentrations may pose significant risks. The results of this study indicate that patients treated with rivanol should be followed to luate the possible longterm effects of this agent.