Modifying effect of 3-amino-1,2,4-triazole on phenobarbital-induced changes in rat liver

On each of two successive days, male rats received ip injections of a mixture of phenobarbital and aminotriazole in isotonic saline. Controls included rats given phenobarbital in saline and rats given only saline. Forty-eight hours after the second treatment, phenobarbital prepared animals showed a marked decrease in zoxazolamine paralysis time, in comparison with the saline controls. The phenobarbital-aminotriazole treated animals displayed a less impressive, but still significant, decrease in paralysis time. At the same interval, hepatic microsomal cytochrome P₄₅₀ was markedly elevated in phenobarbital injected rats, whereas animals given the phenobarbital-aminotriazole mixture exhibited only a slight increment of this cytochrome above the control level. In contrast, both phenobarbital and phenobarbital-aminotriazole treated rats displayed substantial and equivalent increases in liver weight and hepatocellular smooth-surfaced membranes. Identical animals from each treatment category were then challenged with a single dose of carbon tetrachloride (CCl₄). Phenobarbital pretreated rats showed marked enhancement of CCl₄ hepatotoxicity, with massive or submassive hepatic necrosis and a 54% death rate. Animals pretreated with the phenobarbital-aminotriazole mixture, however, had a hepatotoxic reaction comparable to that of the saline controls. Both responded to CCl₄ with a limited centrilobular necrosis and a 12.5% death rate. It was concluded that the difference in hepatotoxic response could not be understood in terms of the structural alterations induced by the drugs. It was considered more likely that this difference was related to variations in hepatic drug-metabolizing enzymes at the time of CCl₄ challenge.