Structural Influences on Pyrrolizidine Alkaloid Induced Cytopathology
Document Type
Article
Journal/Book Title/Conference
Toxicology and Applied Pharmacology
Volume
122
Issue
1
Publisher
Elsevier
Publication Date
1993
First Page
61
Last Page
69
Abstract
Pyrrolizidine alkaloids (PAs), which are common constituents of hundreds of plant species around the world, have been reported to have cytotoxic, carcinogenic, antineoplastic, and genotoxic activity in vivo and in vitro. The exact mechanism of these biological toxicities is not yet clear. The ability of eight PA congeners to inhibit mitosis and induce megalocyte formation in cultured bovine kidney epithelial cells was studied to examine possible structural influences on these endpoints. Representatives of the three PA structural groups, the macrocycles (seneciphylline, senecionine, riddelliine, retrorsine, monocrotaline), open diesters (heliosupine, latifoline), and a necine base (retronecine), were cocultured for 2 hr with a NADPH-generating system and rat liver S9. Macrocylic PAs with αβ-unsaturation (seneciphylline, senecionine, riddelliine, retrorsine) showed a dose-dependent inhibition of colony formation at 50, 100, and 300 μM and induction of megalocytosis at 500 μM. Colony growth resumed 3 weeks after removal of PAs at 50 and 100 μM, and normal cellular morphology returned 5 or 6 weeks after removal of PAs at 500 μM. The saturated macrocyclic (monocrotaline) and open diesters (heliosupine, latifoline), elicited only a slight inhibition of colony formation and had no effect on cellular morphology at 500 μM. The necine base (retronecine) had no effect on either colony formation or cell morphology. Pyrrolic PAs (dehydrosenecionine, dehydromonocrotaline, dehydroretronecine) were more active in inhibition of colony formation than their parent compounds and were potent inducers of abnormal cellular morphology at 500 μM. An N-oxide metabolite, indicine N-oxide, was completely inactive. The results support previous studies showing that there are structural influences on PA-induced cytopathological effects.
Recommended Citation
Kim, H.Y., Stermitz, F.R., Wilson, D.W., Taylor, D. and R.A. Coulombe, Jr. (1993). Structural influences on pyrrolizidine alkaloid induced cytopathology. Toxicol. Appl. Pharmacol. 122: 61-69.
Comments
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