Metabolism, cytotoxicity, and genotoxicity of the pyrrolizidine alkaloid senecionine in primary cultures of rat hepatocytes

Abstract

Senecionine, a pyrrolizidine alkaloid isolated from Senecio vulgaris, was a potent toxicant to primary cultures of adult male rat hepatocytes. A nontoxic dose of [ 14C]senecionine (1.9–2.4 nmol/10 6 cells) was rapidly taken up from the culture medium by hepatocytes and converted to more polar metabolites recovered in the culture medium. Concomitantly some metabolites formed stable covalent bonds with cellular macromolecules. After a 24-hr incubation, 88% of the dose was water soluble while only 10% could be extracted with chloroform; 1.3% of the dose was bound to trichloroacetic acid-precipitated material and could not be extracted with organic solvents. Senecionine was a potent cytotoxin as evidenced by the leakage of lactate dehydrogenase from the hepatocytes into the surrounding culture medium and the loss of cells from the collagen substratum. A linear dose-response relationship for cytotoxicity was obtained for doses ranging from 2.6 to 128 nmol per 10 6 cells. Senecionine was also genotoxic as suggested by the evidence of covalent binding and the stimulation of DNA repair. The lowest dose that stimulated DNA repair was 16 nmol/10 6 cells. Based on these data, one would predict that senecionine is not only a potent hepatotoxin but is also likely to be carcinogenic.