Potentiation of thioacetamide hepatotoxicity by phenobarbital pretreatmentin rats. Inducibility of FAD monooxygenase system and age effect

The ability of phenobarbital to induce the expression and activity of micro somal drug monooxygenases in the liver presents one of the most important i ssues in the held of chemical interactions and in the toxicity of xenobioti cs. The model of rat liver injury induced by a single dose of thioacetamide (500 mg/kg intraperitoneally) was used to study the effect of phenobarbita l (80 mg/kg/day intraperitoneally) for 5 days prior to thioacetamide. Serum parameters of liver injury such as aspartate aminotransferase activity, ga mma-glutamyl transferase activity and the total bilirubin levels, as well a s the activities of hepatic FAD and cytochrome P450 microsomal monooxygenas es, were assayed in 2- and 12-month-old rats. Samples of blood and liver we re obtained from controls (injected at 0 h with 0.5 mi of 0.9% NaCl) and at 12, 24, 48, 72 and 96 h of thioacetamide intoxication either to non-treate d or phenobarbital pretreated rats. Potentiation of thioacetamide hepatotox icity by phenobarbital pretreatment was demonstrated at morphological level , and by significant increases in the activities of serum aspartate aminotr ansferase and gamma-glutamyl transferase, and in the levels of total biliru bin. The extent of potentiation of thioacetamide-induced liver injury by ph enobarbital pretreatment was similar in both age groups. Microsomal FAD mon ooxygenase activity, the enzyme responsible for thioacetamide biotransforma tion, was significantly enhanced (twofold) by phenobarbital pretreatment, a nd also underwent a further increase following thioacetamide, preceding the peak of necrosis. Cytochrome P-450 monooxygenases were induced by phenobar bital pretreatment more than sixfold, and sharply decreased when phenobarbi tal was withdrawn and thioacetamide administered, showing at 48 h intoxicat ion values close to basal. Phenobarbital pretreatment potentiated thioaceta mide necrogenicity, and this potentiation was parallel to the induction of the microsomal FAD monooxygenase system, both by phenobarbital and by thioa cetamide itself The extent of thioacetamide-induced liver injury was signif icantly higher in 12-month-old rats, but the effect of phenobarbital pretre atment was similar in both age groups. (C) 2000 Elsevier Science Ireland Lt d. All rights reserved.