Contrasting effects on halothane hepatotoxicity in the phenobarbital-hypoxia and triiodothyronine model: mechanistic implications.

Factors affecting halothane (H) hepatotoxicity were investigated in two animal models: 1) the phenobarbital-hypoxia model, and 2) the triiodothyronine (T3) model; in the latter we previously have shown that centrilobular necrosis occurs in T3 pretreated rats anesthetized with 1% H, in 21% oxygen for 2 h. Feeding worsens the hepatotoxic effects of H in the T3 model. SGPT levels were higher (P less than 0.001) in T3 pretreated fed animals (641.0 +/- 182.1 U/1) than in T3 pretreated fasted animals (121.9 +/- 30.5 U/1), and histologic grading of hepatic necrosis was more extensive (P less than 0.05) in fed than fasted rats. In contrast, in the phenobarbital-hypoxia model of H hepatotoxicity fasting potentiates the lesion, the severity of histologic grading was worse (P less than 0.001) 24 h after H exposure in fasted than fed rats. Fluoride levels were elevated (P less than 0.001) over control values in the phenobarbital pretreated fasted rats anesthetized with H under hypoxic conditions (15.34 +/- 0.90 microM) but not in T3 pretreated fed rats anesthetized by H in 21% oxygen (2.37 +/- 0.15 microM), indicating that reductive metabolism may not be a prerequisite for toxicity in the T3 model. There was no significant difference in the effect of H and deuterated H on hepatotoxicity in the T3 model. SGPT levels in T3 treated female rats (62.4 +/- 5.1 U/1) were higher (P less than 0.001) than in control female rats (30.5 +/- 1.7 U/1) after H exposure but much less (P less than 0.01) than in male rats (641.0 +/- 182.1 U/1), demonstrating a gender difference for toxicity. These studies show fundamental differences between the two models: 1) hypoxia is required for the phenobarbital-hypoxia model but not for the T3 model; 2) hepatic necrosis correlates with reductive metabolism in the phenobarbital-hypoxia model but not in the T3 model; and 3) nutritional status has important but opposite effects.