Formation of promutagenic methylation damage in tissue-DNA of mice treated with antischistosomal agents

Cancer Lett. 1993 Dec 20;75(3):167-73. doi: 10.1016/0304-3835(93)90059-i.

Abstract

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.

MeSH terms

  • Alkylation
  • Animals
  • DNA / drug effects*
  • DNA Damage*
  • Deoxyguanosine / analogs & derivatives
  • Deoxyguanosine / analysis
  • Hycanthone / adverse effects
  • Hycanthone / pharmacology
  • Kidney / chemistry
  • Kidney / drug effects
  • Liver / chemistry
  • Liver / drug effects
  • Male
  • Methylation
  • Mice
  • Mice, Inbred Strains
  • Oxamniquine / adverse effects
  • Oxamniquine / pharmacology
  • Schistosomicides / adverse effects*
  • Schistosomicides / pharmacology
  • Spleen / chemistry
  • Spleen / drug effects
  • Trichlorfon / adverse effects
  • Trichlorfon / pharmacology
  • Urinary Bladder / chemistry
  • Urinary Bladder / drug effects

Substances

  • Schistosomicides
  • Oxamniquine
  • Hycanthone
  • DNA
  • O(6)-methyl-2'-deoxyguanosine
  • Trichlorfon
  • Deoxyguanosine