Formation of promutagenic methylation damage in tissue-DNA of mice treated with antischistosomal agents.
The existence of the promutagenic methylation damage O6-MedG has been measured at various time intervals in different tissue DNAs of mice received a single therapeutic dose of various antischistosomal agents (hycanthone, oxaminiquine and metrifonate). Liver-DNA exhibited the highest levels of O6-MedG in all treated animals while, spleen DNA contained the lowest. The three antischistosomal agents tested seemed to exert the peak concentrations of their alkylating metabolites over a period of several hours following the administration. In mice which had received hycanthone, liver-DNA contained readily detectable amounts of O6-MedG by 6 h post-treatment (0.089 mol O6-MedG/mol dG) and by the end of 48 h, this was decreased by about 3-fold to reach a level of 0.026 mumol/mol dG. In intestinal-DNA, however, O6-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 O6-MedG was observed at 6 h after administration and at a 24-h time point, the adduct dramatically decreased in the liver and intestine-DNA to undetectable values. In neither tissues was there any evidence for O6-MedG accumulation in the DNA at the end of a 48-h post-treatment. A pattern of O6-MedG, almost similar to that of oxaminiquine, was also observed in tissue-DNA of mice pretreated with metrifonate. These results demonstrate that treatment with antischistosomal agents leads to the formation of highly promutagenic alkylated lesions in the tissue-DNA. The implication of such existence for antischistosomal-induced toxicity and carcinogenicity are discussed.
Badawi
A F
AF
Department of Environmental Studies, Institute of Graduate Studies and Research, Alexandria, Egypt.
Awney
H A
HA
Mostafa
M H
MH
D000478:Alkylation; D000818:Animals; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis; D006826:Hycanthone / Q000009:adverse effects / Q000494:pharmacology; D007668:Kidney / Q000737:chemistry / Q000187:drug effects; D008099:Liver / Q000737:chemistry / Q000187:drug effects; D008297:Male; D008745:Methylation; D051379:Mice; D008815:Mice, Inbred Strains; D010073:Oxamniquine / Q000009:adverse effects / Q000494:pharmacology; D012556:Schistosomicides / Q000009:adverse effects* / Q000494:pharmacology; D013154:Spleen / Q000737:chemistry / Q000187:drug effects; D014236:Trichlorfon / Q000009:adverse effects / Q000494:pharmacology; D001743:Urinary Bladder / Q000737:chemistry / Q000187:drug effects
D012556:Schistosomicides; D010073:Oxamniquine; D006826:Hycanthone; D004247:DNA; C015558:O(6)-methyl-2'-deoxyguanosine; D014236:Trichlorfon; D003849:Deoxyguanosine