Potentiation of thioacetamide-induced hepatotoxicity in alloxan- and streptozotocin-diabetic rats.

Thioacetamide-induced hepatoxicity was potentiated in male Sprague-Dawley rats rendered diabetic by alloxan or streptozotocin. The response was more striking in alloxan-diabetic rats. Insulin administration prevented the potentiation following alloxan pretreatment. Fasting also resulted in an enhanced hepatotoxic response to thioacetamide, but the increase was much less than that observed in rats given the diabetogenic agents. The ketosis produced by alloxan was more severe than that induced by streptozotocin, but was unlike that caused by fasting. Pretreatment with phenobarbital, 3-methylcholanthrene or 3,4-benzpyrene did not enhance thioacetamide liver injury.

Effects of diazepam on the biliary excretion of diphenylhydantoin in the rat.

Studies were performed to examine the effects of diazepam (DZP) on the biliary excretion of diphenylhydantoin (DPH, phenytoin) in the rat. One-hour pretreatment with DZP (150 mg/kg i.p. or 10 mg/kg i.v.) markedly suppressed the rates as well as the cumulative amounts of radioactivity excreted in bile after administration of 14C-DPH (70, 35 or 10 mg/kg i.v.). No changes in bile flow were apparent and the decreases in biliary excretion were not accompanied by increases in the urinary elimination of the drug or its metabolites. Disappearance of DPH from plasma and tissue were also reduced, and at 4 and 6 hours after DPH administration higher plasma and tissue concentrations were encountered in the DZP-treated group. The possible mechanisms by which DZP pretreatment altered the biliary excretion and the tissue distribution of DPH were examined; studies in vitro were correlated with the in vivo findings. DPH hepatic uptake and storage were apparently unaffected by DZP treatment, but liver/bile concentration ratios were suppressed. However, a direct competition between the two drugs for biliary transport was not evident. Further studies showed that liver microsomes from rats treated with DZP metabolized DPH in vitro less effectively than those from control rats. The metabolism of DPH was more markedly inhibited by the direct addition of DZP to the incubation mixtures in concentrations greater than 0.05 mM. Therefore, it appears that the effect of DZP on the metabolism of DPH is responsible for most of the observed effect although other mechanisms, including a direct effect on hepatocyte function, cannot be completely ruled out.

Ethylene dichloride: the influence of disulfiram or ethanol on oncogenicity, metabolism, and DNA covalent binding in rats.

Male and female Sprague-Dawley rats were exposed to 50 ppm ethylene dichloride (EDC) for 7 hr/day, 5 days/week, for 2 years by inhalation. Additional rats were exposed to 50 ppm EDC either with 0.05% disulfiram in the diet or with 5% ethanol in the drinking water. Histopathologic lesions related to the combination of inhaled EDC and dietary disulfiram were observed in the liver, mammary, and testicular tissues of rats. This combined exposure resulted in a significant increase in the incidence of intrahepatic bile duct cholangiomas in both male and female rats. Male rats exposed to both EDC and disulfiram also had an increased incidence of subcutaneous fibromas, neoplastic nodules, and interstitial cell tumors in the testes. The female rats exposed to EDC and disulfiram also had a higher incidence of mammary adenocarcinomas. No significant increase in the number of any tumor type was observed in rats exposed to only EDC, disulfiram, or ethanol. Similarly, no significant increase in the number of tumors was observed in rats exposed to inhaled EDC and ethanol in water. At the end of the 2-year period animals from each group were evaluated for EDC metabolism and DNA binding. Blood levels of EDC at the end of a 7-hr exposure period were significantly higher for rats exposed to both EDC and disulfiram than for rats exposed to EDC alone. In addition, the elimination of a single oral dose of radiolabeled EDC was affected. The urinary excretion of 14C from control rats was 47 to 55% of the administered dose with 28 to 30% detected as unchanged EDC in the breath. In disulfiram-treated rats, only 35 to 36% of the administered 14C was eliminated in the urine with 41 to 55% as unchanged EDC in the breath. The urinary metabolite HPLC profile was qualitatively unchanged by long-term EDC, disulfiram, or ethanol treatment, either alone or in combination, and consisted primarily of thiodiglycolic acid, thiodiglycolic acid sulfoxide, and chloroacetic acid.