Effects of either a single (300 mg/kg) or a subchronic (0.3 and 0.6% for 70 days) oral administration of a dithiocarbamate fungicide (zinc ethylene-bis-dithiocarbamate, zineb) on hepatic drug metabolism and on the activity of several glutathione-dependent enzymes were investigated in male New Zealand White rabbits. While a pronounced reduction in the rate of oxidative biotransformations occurred after either single or repeated exposure, both cytochrome P450 and total haem content were lowered following acute challenge to zineb. None of the experimental protocols affected microsomal carboxylesterase but induced a marked increase in glutathione content and none of the examined glutathione-dependent enzymes was altered by the single administration of zineb, whereas the subchronically exposed rabbits showed a fall in the activities of both total glutathione S-transferase and selenium-independent glutathione peroxidase. In the 0.6% treated animals, a decrease in class mu glutathione S-transferase and glyoxalase I, and an increase in thiol-transferase activities were also recorded. It is concluded that (1) zineb is able to selectively impair oxidative drug metabolism with possible 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.

No abstract

The purpose of this study was to determine whether subchronic (70 days) oral exposure to moderate to high levels of triphenyltin acetate (TPTA), an organotin derivative used worldwide, would affect the microsomal hepatic and renal drug-metabolizing enzymes in rabbits and lambs. Rabbits were offered a diet containing 0, 15, 75 or 150 ppm TPTA, while lambs were daily given 0, 1.5 or 7.5 mg TPTA per kg bw. The tin content in the liver and kidneys was measured by atomic absorption spectrophotometry. In the rabbits' livers, TPTA failed to affect the cytochrome P450 content, or the oxidative, hydrolytic (carboxylesterase) or conjugative (UDPG-transferase) enzyme activities studied. In contrast, a striking dose-related increase in both P450 content and carboxylesterase activity (up to 280%) was detected in the rabbits' kidneys, but the ECOD and EROD activities were respectively unchanged or moderately depressed. None of the enzymes studied showed statistically significant changes in the ovine hepatic or renal subfractions. The results suggest that repeated exposure to TPTA could lead to the induction of a particular P450-isoenzyme in rabbit kidneys which is concerned with the metabolism of endogenous compounds (e.g. steroids, prostaglandins, thromboxanes). The lack of significant tissue- and species-related differences in the concentration of tin supports the hypothesis that the changes observed in the rabbits' kidneys may not have been caused solely by the accumulation of the metal in the tissues.

No abstract

No abstract