INHIBITION OF HEPATIC XENOBIOTIC METABOLISM AND OF GLUTATHIONE-DEPENDENT ENZYME-ACTIVITIES BY ZINC ETHYLENE-BIS-DITHIOCARBAMATE IN THE RABBIT

Effects of either a single (300 mg/kg) or a subchronic (0.3 and 0.6% f or 70 days) oral administration of a dithiocarbamate fungicide (zinc e thylene-bis-dithiocarbamate. zineb) on hepatic drug metabolism and on the activity of several glutathione-dependent enzymes were investigate d in male New Zealand White rabbits. While a pronounced reduction in t he rate of oxidative biotransformations occurred after either single o r repeated exposure, both cytochrome P450 and total haem content were lowered following acute challenge to zineb. None of the experimental p rotocols affected microsomal carboxylesterase but induced a marked inc rease in glutathione content and none of the examined glutathione-depe ndent enzymes was altered by the single administration of zineb, where as the subchronically exposed rabbits showed a fall in the activites o f both total glutathione S-transferase and selenium-independent glutat hione peroxidase. In the 0.6% treated animals, a decrease in class mu glutathione S-transferase and glyoxalase 1, and an increase in thiol-t ransferase activities were also recorded. It is concluded that (1) zin eb is able to selectively impair oxidative drug metabolism with possib le different mechanism(s) according to the duration of the exposure, ( 2) only the subchronic treatment affects glutathione-dependent enzymes , (3) the decrease in glutathione S-transferase activity would seem to be ascribed to a direct interaction with the fungicide.