O-6-METHYLGUANINE AND O-6-METHYLGUANINE-DNA METHYLTRANSFERASE ACTIVITY IN TISSUES OF BDF-1 MICE TREATED WITH ANTIPARASITIC DRUGS

Levels of the DNA promutagenic methylation damage, O-6-methylguanuine (O-6-MeG) and the activity of the O-6-methylguanuine-DNA methyltransfe rase (MGMT), the enzyme responsible for repairing O-6-MeG, were measur ed at various time intervals in tissues of BDF-1 mice administered a s ingle therapeutic dose of the antischistosomal agents hycanthone, oxam iniquine and metrifonate. Hycanthone increased O-6-MeG in the liver-DN A after 6 h, then decreased by 3-fold after 48 h. Lower levels of the adduct and a slower rare of formation were found in the intestine and bladder. MGMT activities were significantly lower in the liver (74%) a nd bladder (25%) compared to control animals after 6 h, then restored by 48 h. Oxaminiquine increased O-6-MeG in all tissues, but spleen, af ter 6 h and persisted only in the bladder after 48 h. Liver and bladde r tissues of these animals exhibited a pattern of alteration in the MG MT activity similar to that observed for hycanthone. Metrifonate induc ed a profile of O-6-MeG comparable to that of oxaminiquine but the lev els of the adduct were about 2-fold lower. Hepatic MGMT in these anima ls was significantly lower (similar to 38%) than the control values af ter 6 h, then restored by 48 h. A significant negative correlation was obtained between O-6-MeG and MGMT activity in the liver (r = -0.85), intestine (r = -0.62) and bladder (r = -0.59). These results demonstra te that treatment with antischistosomal agents may lead to the formati on of promutagenic alkylation damage in the tissue DNA and alterations in the DNA repair capacity. (C) 1998 Elsevier Science Ireland Ltd. Al l rights reserved.