A comparison of the pneumotoxicity of some pyrrolic esters and similar compounds analogous to pyrrolizidine alkaloid metabolites, given intravenously to rats.

Toxic effects of 14 esters with chemical properties similar to those of pyrrolic pyrrolizidine alkaloid metabolites, were investigated in rats. The compounds were either mono- or bifunctional alkylating agents. When single doses were injected into a tail vein, the lungs were the main organ affected. All but one of the compounds tested caused pulmonary oedema and congestion, accompanied by pleural effusion, and animals often died between 1 and 2 days after the injection. Smaller amounts of some of the esters caused a characteristic chronic lung lesion, with proliferation of alveolar tissue, resembling that produced by the pyrrolizidine alkaloids fulvine and monocrotaline. All the compounds which caused death associated with chronic lung damage were bifunctional alkylating agents. Very large doses, especially when injected rapidly, sometimes caused death within a few minutes. The results confirmed that the ability to damage the lungs, and sometimes the heart, is a property of certain esters capable of alkylating tissues with which they come into contact, and is dependent on the chemical reactivity rather than the molecular structure of the compound. Nevertheless the latter may play a part, as shown by the exceptionally high pneumotoxicity of an indole ester having a lipophilic structure with high affinity for tissue. Necrosis of the liver in some rats might be due to metabolites formed in the liver from the injected compounds or their decomposition products, rather than the active esters themselves.