O6-methylguanine and O6-methylguanine-DNA [corrected] methyltransferase activity in tissues of BDF-1 mice treated with antiparasitic drugs.
Levels of the DNA promutagenic methylation damage, O6-methylguanine (O6-MeG) and the activity of the O6-methylguanine-DNA methyltransferase (MGMT), the enzyme responsible for repairing O6-MeG, were measured at various time intervals in tissues of BDF-I mice administered a single therapeutic dose of the antischistosomal agents hycanthone, oxaminiquine and metrifonate. Hycanthone increased O6-MeG in the liver-DNA after 6 h, then decreased by 3-fold after 48 h. Lower levels of the adduct and a slower rate 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 O6-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 O6-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 (approximately 38%) than the control values after 6 h, then restored by 48 h. A significant negative correlation was obtained between O6-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.[1]References
- O6-methylguanine and O6-methylguanine-DNA [corrected] methyltransferase activity in tissues of BDF-1 mice treated with antiparasitic drugs. Badawi, A.F. Toxicol. Lett. (1998) [Pubmed]
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