Inhibition of hepatic drug-metabolizing enzymes by thiophaophate insecticides and its toxicological evaluation.

Abstract

Thiophosphate insecticides, fenitrothion, diazinon and methylparathion, inhibit hepatic drug-metabolizing enzyme activity which was assayed using aminopyrine and aniline as substrates. About 50% inhibition was observed 4 hrs after the injection of fenitrothion into mice in a dose of 25 mg/kg. The addition in vitro of thiophosphates into a reaction mixture of drug metabolizing enzyme also produced an effective inhibition and IC50 was around 10(-5)M for fenitrothion. DDVP and oxygenated metabolite of fenitrothion did not show any inhibiting effect either in vitro or in vivo. The inhibition of thiophosphates in vitro was competitive while the kinetics of in vivo inhibition was shown as non-competitive. The drug metabolism in the rat liver preparation was also inhibited by thiophosphate in vitro, but in vivo treatment to male rats resulted in only slight inhibition. Female rats exhibited the similar response as mice. The administration of fenitrothion to mice prolonged the hexobarbital sleeping time and, consequently, suppressed the oxidative metabolism of parathion in liver preparation. These effects reveal that the biological half life of thiophosphate insecticides could be altered by the mode of administration or by co-existing thiophosphates.