Structural Influences on Pyrrolizidine Alkaloid-Induced Cytopathology

H. Y. Kim, F. R. Stermitz, R. J. Molyneux, Dennis W Wilson, D. Taylor, R. A. Coulombe

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)61-69
Number of pages9
JournalToxicology and Applied Pharmacology
Volume122
Issue number1
DOIs
StatePublished - Sep 1993

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Pyrrolizidine Alkaloids
Monocrotaline
indicine-N-oxide
Metabolites
NADP
Mitosis
Liver
Antineoplastic Agents
Oxides
Toxicity
Rats
Epithelial Cells
Kidney

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

Structural Influences on Pyrrolizidine Alkaloid-Induced Cytopathology. / Kim, H. Y.; Stermitz, F. R.; Molyneux, R. J.; Wilson, Dennis W; Taylor, D.; Coulombe, R. A.

In: Toxicology and Applied Pharmacology, Vol. 122, No. 1, 09.1993, p. 61-69.

Research output: Contribution to journalArticle

Kim, H. Y. ; Stermitz, F. R. ; Molyneux, R. J. ; Wilson, Dennis W ; Taylor, D. ; Coulombe, R. A. / Structural Influences on Pyrrolizidine Alkaloid-Induced Cytopathology. In: Toxicology and Applied Pharmacology. 1993 ; Vol. 122, No. 1. pp. 61-69.
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