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.
Badawi
A F
AF
Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Ontario, Canada. a.badawi@utoronto.ca
D000818:Animals; D004249:DNA Damage; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006826:Hycanthone / Q000008:administration & dosage / Q000633:toxicity; D007422:Intestines / Q000187:drug effects* / Q000201:enzymology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D016296:Mutagenesis / Q000187:drug effects; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics / Q000378:metabolism*; D010073:Oxamniquine / Q000008:administration & dosage / Q000633:toxicity; D012556:Schistosomicides / Q000633:toxicity*; D014236:Trichlorfon / Q000008:administration & dosage / Q000633:toxicity; D001743:Urinary Bladder / Q000187:drug effects* / Q000201:enzymology
D012556:Schistosomicides; D010073:Oxamniquine; D006826:Hycanthone; D006147:Guanine; C008449:O-(6)-methylguanine; D014236:Trichlorfon; D019853:O(6)-Methylguanine-DNA Methyltransferase