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Characterization of Hepatic DNA Damage Induced in Rats by the Pyrrolizidine Alkaloid Monocrotaline¹

Departments of Pharmacology and Toxicology [T. W. P., G. T. B., I. G. S.], Radiation Oncology [G. T. B.], and Pharmacology [R. J. H., I. G. S.], University of Arizona, Health Sciences Center, Tucson, Arizona 85724

Hepatic DNA damage induced by the pyrrolizidine alkaloid monocrotaline was evaluated following i.p. administration to adult male Sprague-Dawley rats. Animals were treated with various doses ranging upward from 5 mg/kg, and hepatic nuclei were isolated 4 hr later. Hepatic nuclei were used as the DNA source in all experiments. DNA damage was characterized by the alkaline elution technique. A mixture of DNA-DNA interstrand cross-links and DNA-protein cross-links was induced. Following an injection of monocrotaline, 30 mg/kg i.p., DNA-DNA interstrand cross-linking reached a maximum within 12 hr or less and thereafter decreased over a protracted period of time. By 96 hr postadministration, the calculated cross-linking factor was no longer statistically different from zero. No evidence for the induction of DNA single-strand breaks was observed, although the presence of small numbers of DNA single-strand breaks could have been masked by the overwhelming predominance of DNA cross-links. These DNA cross-links may be related to the hepatocarcinogenic, hepatotoxic, and/or antimitotic effects of monocrotaline.

¹ This work was supported in part by National Research Service Award CA-09213 and by NIH Grant HL-25258.

² To whom requests for reprints should be addressed.

Received 8/18/83. Accepted 1/10/84.