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Nyska, A. et al.

Nyska, Moomaw, Foley, Maronpot, Malarkey, Cummings, Peddada, Moyer, Allen, Travlos, Chan,

The hepatic endothelial carcinogen riddelliine induces endothelial apoptosis, mitosis, S phase, and p53 and hepatocytic vascular endothelial growth factor expression after short-term exposure.

Riddelliineis a naturally occurring pyrrolizidine alkaloid found in certain poisonous rangeland plants of the western United States. In National Toxicology Program 2-year studies, riddelliine induced high incidences of hemangiosarcoma in the liver of F344/N rats (both sexes) and B6C3F1 mice (males). To understand this pathogenesis, we tested short-term effects of riddelliine. Three groups (control; 1.0 mg/kg/day, high dose used in the 2-year study; and 2.5 mg/kg/day) of seven male F344/N rats per group were terminated after 8 consecutive doses and 30 doses (6 weeks, excluding weekends). Serum vascular endothelial growth factor (VEGF), histological, immunohistochemical [factor VIII-related antigen/von Willebrand factor (fVIII-ra/vWf)], VEGF, VEGF receptor-2 (VEGFR2), glutathione S-transferase-pi, S-phase (BrdU), p53, apoptosis, and ultrastructural evaluations were performed on the liver. Following 8 doses of 1.0 and 2.5 mg/kg/day, increased numbers of apoptotic and S-phase nuclei appeared in hepatocytes and endothelial cells. Following 30 doses of 1.0 and 2.5 mg/kg/day, hepatocytes exhibited reduced mitosis, fewer S-phase nuclei, increased hypertrophy, and fatty degeneration, while endothelial cells showed karyomegaly, cytomegaly, decreased apoptosis, more S-phase nuclei, and p53 positivity. Hepatocytes of treated animals expressed higher VEGF immunopositivity. That altered endothelial cells were fVIII-ra/vWf and VEGFR2 positive confirmed their identity. These changes may have promoted hemangiosarcoma development upon long-term exposure through endothelial adduct formation, apoptosis, proliferation of endothelial cells having undamaged and/or damaged DNA, and mutation. Endothelial proliferation may also have been promoted through endothelial arrest at S phase, which was associated with endothelial karyo- and cytomegaly, resulting in hepatocytic hypoxia, triggering VEGF induction.[1]

References

The hepatic endothelial carcinogen riddelliine induces endothelial apoptosis, mitosis, S phase, and p53 and hepatocytic vascular endothelial growth factor expression after short-term exposure. Nyska, A., Moomaw, C.R., Foley, J.F., Maronpot, R.R., Malarkey, D.E., Cummings, C.A., Peddada, S., Moyer, C.F., Allen, D.G., Travlos, G., Chan, P.C. Toxicol. Appl. Pharmacol. (2002) [Pubmed]

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