FORMATION OF PROMUTAGENIC METHYLATION DAMAGE IN TISSUE-DNA OF MICE TREATED WITH ANTISCHISTOSOMAL AGENTS

The existence of the promutagenic methylation damage O-6-MedG has been measured at various time intervals in different tissue DNAs of mice r eceived a single therapeutic dose of various antischistosomal agents ( hycanthone, oxaminiquine and metrifonate). Liver-DNA exhibited the hig hest levels of O-6-MedG in all treated animals while, spleen DNA conta ined the lowest. The three antischistosoml agents tested seemed to exe rt the peak concentrations of their alkylating metabolites over a peri od of several hours following the administration. In mice which had re ceived hycanthone, liver-DNA contained readily detectable amounts of O -6-MedG by 6 h post-treatment (0.089 mol O-6-MedG/mol dG) and by the e nd of 48 h, this was decreased by about 3-fold to reach a level of 0.0 26 mu mol/mol dG. In intestinal-DNA, however, O-6-MedG was formed more slowly and contained about half the level of that found in the liver- DNA. In the tissue-DNA of animals which had received oxaminiquine, the highest level of O-6-MedG was observed at 6 h after administration an d at a 24-h time point, the adduct dramatically decreased in the liver and intestine-DNA to undetectable values. In neither tissues was ther e any evidence for O-6-MedG accumulation in the DNA at the end of a 48 -h post-treatment. A pattern of O-6-MedG, almost similar to that of ox aminiquine, was also observed in tissue-DNA of mice pretreated with me trifonate. These results demonstrate that treatment with antischistoso mal agents leads to the formation of highly promutagenic alkylated les ions in the tissue-DNA. The implication of Such existence for antischi stosomal-induced toxicity and carcinogenicity are discussed.