engleski

The influence of radioprotective drug WR-2721 on acute hepatotoxicity in mouse

It is known that WR-2721 (S-2-(3-aminopropylamino)ethyl acid) have radioprotective and chemoprotrctive effects on non-tumor tissues (Treskes et al., Cancer Chemotherapy & Pharmacology.33:93-106, 1993.), and is now introduced into clinical tumor therapy protocols. We investigated whether WR-2721 have a protective role in other kinds of tissue injuri, i.e. acute liver injuri induced with acetaminophen (AAP). CBA/H Zgr inbred mice of both sexes aged 12-16 weeks, weighing 20-25 g were used. Mice were given phenobarbitone-sodium (Kemika, Zagreb, Croatia) in drinking water during 7 days (300 mg/kg) in order to induce hepatic drug -metabolizing enzymes. Thereafter, mice were feasted overnight and WR-2721 was given i.p. (50, 100 or 200 mg/kg). After 15-30 minutes they received acetaminophen (Paracetamol ; AAP) 200 mg/kg by gastric tube. Animals were alowed water 4 hours later. The mortality of mice was followed for 3 days and serum aminotransferase levels were determined 24 hours after AAP administration. Survival of mice was prolonged after all doses of WR-2721, but significantly only after the dose of 100 mg/kg of WR-2721. Similarly, the pretreatment of mice with 100 mg/kg of WR-2721 highly significantly reduced serum aspartate aminotransferase levels (AST, p<0, 0005) and serum alanine aminotransferase levels (ALT, p<0.005). The doses of 50 and 200 mg/kg of WR-2721 also reduced AST and ALT, but not significantly. These data shows that WR-2721 has definitive hepatoprotective effect, but only in very restricted dose range. Possible explanation for this may be that the lowest dose of WR-2721 is not enough protective, while the highest dose of WR-2721 may be hepatotoxic by itself, thus causing additional liver damage along with AAP. We are continuing our experiments in that direction.

WR-2721; hepatotoxicity; acetaminophen

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