The conversion of the pyrrolizidine alkaloid retrorsine to pyrrolic derivatives in vivo and in vitro and its acute toxicity to various animal species

Abstract

1. (1)|The acute toxicity of retrorsine to mice, hamsters, guinea pigs, fowl and quail has been determined. Approximate LD 50 values varied from 65 mg/kg in the mouse to 279 mg/kg in quail. 2. (2)|Guinea pigs were resistant to retrorsine up to 800 mg/kg. Phenobarbitone pretreatment increased the liver microsomal conversion of retrorsine to pyrrolic metabolites in vitro, the liver levels of bound pyrrolic metabolites formed from retrorsine in vivo and the susceptibility of guinea pigs to the acute hepatotoxic effects of retrorsine. 3. (3)|Phenobarbitone pretreatment of mice increased the liver microsomal conversion of retrorsine to pyrrolic metabolites in vitro but decreased the liver levels of bound pyrroles and decreased the susceptibility of mice to acute hepatotoxic effects of the alkaloid. 4. (4)|Liver pyrrole levels measured 2 h after similar intraperitoneal doses of retrorsine were generally high in susceptible species and low in more resistant ones. 5. (5)|Enzymatic activities of liver microsomal preparations converting retrorsine to pyrrolic metabolites in vitro varied considerably between species but did not always correlate with the levels of bound pyrrolic metabolites formed in vivo following the administration of retrorsine.