Potentiation of thioacetamide hepatotoxicity by phenobarbital pretreatment in rats. Inducibility of FAD monooxygenase system and age effect.
The ability of phenobarbital to induce the expression and activity of microsomal drug monooxygenases in the liver presents one of the most important issues in the field of chemical interactions and in the toxicity of xenobiotics. The model of rat liver injury induced by a single dose of thioacetamide (500 mg/kg intraperitoneally) was used to study the effect of phenobarbital (80 mg/kg/day intraperitoneally) for 5 days prior to thioacetamide. Serum parameters of liver injury such as aspartate aminotransferase activity, gamma-glutamyl transferase activity and the total bilirubin levels, as well as the activities of hepatic FAD and cytochrome P450 microsomal monooxygenases, were assayed in 2- and 12-month-old rats. Samples of blood and liver were obtained from controls (injected at 0 h with 0.5 ml of 0.9% NaCl) and at 12, 24, 48, 72 and 96 h of thioacetamide intoxication either to non-treated or phenobarbital pretreated rats. Potentiation of thioacetamide hepatotoxicity by phenobarbital pretreatment was demonstrated at morphological level, and by significant increases in the activities of serum aspartate aminotransferase and gamma-glutamyl transferase, and in the levels of total bilirubin. The extent of potentiation of thioacetamide-induced liver injury by phenobarbital pretreatment was similar in both age groups. Microsomal FAD monooxygenase activity, the enzyme responsible for thioacetamide biotransformation, was significantly enhanced (twofold) by phenobarbital pretreatment, and also underwent a further increase following thioacetamide, preceding the peak of necrosis. Cytochrome P450 monooxygenases were induced by phenobarbital pretreatment more than sixfold, and sharply decreased when phenobarbital was withdrawn and thioacetamide administered, showing at 48 h intoxication values close to basal. Phenobarbital pretreatment potentiated thioacetamide necrogenicity, and this potentiation was parallel to the induction of the microsomal FAD monooxygenase system, both by phenobarbital and by thioacetamide itself. The extent of thioacetamide-induced liver injury was significantly higher in 12-month-old rats, but the effect of phenobarbital pretreatment was similar in both age groups.
Zaragoza
A
A
Instituto de Bioquímica (CSIC-UCM), Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
Andrés
D
D
Sarrión
D
D
Cascales
M
M
D000367:Age Factors; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D001711:Biotransformation; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009336:Necrosis; D010105:Oxygenases / Q000096:biosynthesis*; D010634:Phenobarbital / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013853:Thioacetamide / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D005723:gamma-Glutamyltransferase / Q000097:blood
D013853:Thioacetamide; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D001663:Bilirubin; D010634:Phenobarbital