O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE ACTIVITY IN TISSUES OF MICE TREATED WITH ANTISCHISTOSOMAL AGENTS

The activity of O-6-alkylguanine-DNA alkyl transferase (ATase), the en zyme responsible for repairing promutagenic methylation damage in DNA, was measured at various time intervals in tissue extracts of mice adm inistered (in vivo) a single therapeutic dose of the antischistosomal agents hycanthone, oxaminiquine and metrifonate. In control animals, l iver contained the highest levels of ATase activity (15.8+/-1.8 fmole ATase/mu g DNA) followed by spleen (11.0+/-1.7 fmole/mu g DNA), intest ine (2.3+/-0.3 fmole/mu g DNA) and bladder (0.22+/-0.04 fmole/mu g DNA ). With hycanthone, ATase activity was reduced by 6 and 24 h post trea tment to 74% and 27% below the control value, respectively. Bladder ex hibited a 25% inactivation in the ATase level at 6 h time point. Splee n and bladder did not show any alteration in the ATase activity. In an imals administered oxaminiquine, liver and bladder had a near identica l pattern to that observed for hycanthone. Spleen and intestine, howev er, revealed activation in ATase by 50% and 42%, respectively after 6 h of treatment. This activation was also observed in the bladder of me trifonate-treated mice. In a previous study (Badawi et al, Cancer Lett 75: 167, 1993), DNA-alkylation damage (O-6-methyldeoxyguanosine; O-6- MedG) was evaluated in these tissues and there was an inverse correlat ion between the levels of methylation damage and ATase activity in liv er (r=-0.85, p<0.01), intestine (r=-0.62, p<0.01) and bladder (r=-0.59 , p<0.05).