Genotoxicity and cytotoxicity of selected pyrrolizidine alkaloids, a possible alkenal metabolite of the alkaloids, and related alkenals.

Recently our laboratory isolated trans-4-OH-2-hexenal from the hepatic microsomal metabolism of the macrocyclic pyrrolizidine alkaloid (PA) senecionine and demonstrated in vivo that hepatic necrosis occurred following injection into the hepatic portal vein. To demonstrate similarities in the toxic effects of these compounds, as well as additional macrocyclic PAs and alkenals, genotoxicity and cytotoxicity were examined in primary cultures of rat hepatocytes. A positive cytotoxic response was exhibited by senecionine, retrorsine, seneciphylline, 19-OH-senecionine, trans-4-OH-2-hexenal, trans-4-OH-2-nonenal, and nonenal as measured by the release of LDH. A weaker response was elicited by hexenal. Dosages used of each of these compounds ranged from 30 to 600 nmol/10(6) cells, with each compound exhibiting a linear dose response within this range. All eight compounds exhibited a positive, dose-related genotoxic response as measured by autoradiographic detection of unscheduled DNA synthesis. These results would predict a carcinogenic role for both the PAs and the alkenals. This would suggest similarities in the mechanisms of action of the PAs and alkenals, lending support to the proposed role of trans-4-OH-2-hexenal as an important toxic metabolite of the PAs.