This current study was to investigate the in vitro cytotoxicity of rat hepatocytes induced by the antifungal drugs, itraconazole and fluconazole. Both antifungal drugs caused dose-dependent cytotoxicity. In vitro incubation of hepatocytes with itraconazole revealed significantly higher lactate dehydrogenase (LDH) leakage when compared to fluconazole. Phenobarbital pretreated hepatocytes contained significantly higher total cytochrome P450 content than the control hepatocytes. P450 content was reduced approximately 30% for both types of hepatocytes after 6 hours incubation. Interestingly, cytotoxicity of itraconazole was reduced significantly by phenobarbital pretreatment. Phenobarbital did not have any effect on the cytotoxicity induced by fluconazole. These results demonstrate the in vitro toxicity of hepatocytes induced by itraconazole and fluconazole that were expressed in a dose- and time-dependent manner. Phenobarbital plays a role in the cytoprotection of hepatocytes to itraconazole-induced but not fluconazole-induced cytotoxicity in vitro.
The effect of phenobarbitone against signal grass (Brachiaria decumbens) toxicity was studied in 26 male crossbred sheep. Grazing on signal grass significantly decreased the concentration of cytochrome P-450 and the activity of drug metabolizing enzymes, viz. aminopyrine-N-demethylase, aniline-4-hydroxylase, UDP- glucuronyltransferase and glutathione-S-transferase in liver and kidneys of affected sheep.Oral administration of phenobarbitone (30 mg/kg body weight) for five consecutive days before grazing on B. decumbens pasture, and thereafter, for three consecutive days every two weeks, resulted in significant increases in hepatic and renal activities of drug-metabolizing enzymes. The induction of drug metabolizing activity in sheep grazing on signal grass group was found to be lower than in animals given phenobarbitone alone. Induction by phenobarbitone provided a degree of protection against the toxic effects of B. decumbens as indicated by the delay in the appearance of signs of toxicity. Furthermore, these were much milder compared to those in the sheep not treated with phenobarbitone. The present study suggests that phenobarbitone-type cytochrome P-450 isoenzyme-induction may increase resistance against signal grass (B. decumbens) toxicity in sheep.