Metabolism and toxicity of anacrotine, a pyrrolizidine alkaloid, in rats.
The effects of anacrotine, a pyrrolizidine alkaloid (PA) which has the structure of senecionine with an additional 6-hydroxy group, have been investigated in weanling male rats. When anacrotine was given i.p. (100 mg/kg), pyrrolic metabolites reached a peak level in the liver during the first 0.5 h, then fell rapidly to a lower level which subsequently declined more slowly. Pyrrolic metabolites accumulated in the lungs during the first hour to a level which then remained relatively steady for at least 4 h. The lung level of pyrrolic metabolites after 2 h was about 39% of the liver level, compared with 16% in rats given senecionine. Anacrotine caused acute centrilobular necrosis and congestion of the liver when 125 mg/kg or more was given i.p., but oral doses (up to 180 mg/kg) caused relatively little liver necrosis. Enlarged hepatocytes developed during ensuing weeks, but these were moderate compared with the bizarre giant cells often associated with pyrrolizidine intoxication. In contrast, anacrotine produced much more severe lung damage than most other pyrrolizidine alkaloids. The lungs were affected by i.p. or oral doses well below those needed to produce acute liver damage. Pulmonary congestion and oedema, extensive necrosis of the pulmonary endothelium, and thickening of alveolar septae, developed within 2 days after dosing. After single i.p. doses of 60 mg/kg or more progressive consolidation of lung tissue often led to death after 2-5 weeks. Hearts showed myocardial necrosis of the right ventricular wall. Dehydroanacrotine, the putative reactive pyrrolic metabolite of anacrotine, given i.v. to rats, caused dose-related chronic lung and heart damage identical to that produced by anacrotine, but after lower doses (6-27 mg/kg); larger amounts caused acute lung damage. It is suggested that the severe lung damage in animals given anacrotine is due to dehydroanacrotine, formed in the liver. This metabolite is more stable than the pyrrolic derivatives of most other pyrrolizidine alkaloids, and it is thus able to reach the lungs in relatively large amounts.
D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury; D007700:Kinetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D009206:Myocardium / Q000473:pathology; D009336:Necrosis; D011763:Pyrrolizidine Alkaloids / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D011763:Pyrrolizidine Alkaloids; C009237:senecionine