O6-methylguanine and O6-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 methyltransferase (MGMT), the enzyme responsible for repairing O-6-MeG, were measured at various time intervals in tissues of BDF-1 mice administered a single therapeutic dose of the antischistosomal agents hycanthone, oxaminiquine and metrifonate. Hycanthone increased O-6-MeG in the liver-DNA 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%) and bladder (25%) compared to control animals after 6 h, then restored by 48 h. Oxaminiquine increased O-6-MeG in all tissues, but spleen, after 6 h and persisted only in the bladder after 48 h. Liver and bladder tissues of these animals exhibited a pattern of alteration in the MGMT activity similar to that observed for hycanthone. Metrifonate induced a profile of O-6-MeG comparable to that of oxaminiquine but the levels of the adduct were about 2-fold lower. Hepatic MGMT in these animals was significantly lower (similar to 38%) than the control values after 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 demonstrate that treatment with antischistosomal agents may lead to the formation of promutagenic alkylation damage in the tissue DNA and alterations in the DNA repair capacity. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.