Role of metabolism in the immediate effects and pneumotoxicity of 3-methylindole in goats.

Rapid infusion of 3-methylindole (3-MI) dissolved in 10% Cremophor EL in water was immediately followed by pulmonary arterial hypertension, systemic arterial hypotension, decreased minute volume and periods of apnoea in goats. Rapid intravenous infusion of Cremophor EL/water alone caused similar immediate effects to those of Cremophor EL plus 3-MI in various dosages. Pretreatment of goats with piperonyl butoxide or phenobarbitone did not significantly alter these immediate cardiopulmonary responses. But pretreatment with piperonyl butoxide prevented clinical signs and pulmonary lesions of 3-MI toxicity, whereas phenobarbitone pretreatment shortened survival time and enhanced pulmonary pathology. Cremophor EL and 3-MI dissolved in Cremophor EL caused severe in vitro haemolysis of caprine and bovine erythrocytes. There was no relationship between the immediate effects of 3-MI and the subsequent development of 3-MI-induced pneumotoxicity and deaths in control goats or in goats pretreated with piperonyl butoxide or phenobarbitone. Induction or inhibition of mixed function oxidase activity had no influence on immediate responses to 3-MI but did change the severity of clinical and pathological responses. It is concluded that there is no apparent relationship between the immediate and the pneumotoxic effects of 3-MI. It is possible that the immediate effects are the result of intravascular haemolysis.