Riddelliine N-oxide is a phytochemical and mammalian metabolite with genotoxic activity that is comparable to the parent pyrrolizidine alkaloid riddelliine

Pyrrolizidine alkaloids (PAs) and their N-oxide derivatives are naturally-formed genotoxic phytochemicals that are widely distributed throughout the world. Although, the quantities of PAs and PA N-oxides in plants are nearly equal, the biological and genotoxic activities of PA N-oxides have not been studied extensively. PA N-oxides are major metabolites of PAs and are generally regarded as detoxification products. However, in this study, we report that rat liver microsomes converted riddelliine N-oxide to the genotoxic 6.7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP) metabolite. Metabolism of riddellime N-oxide by rat liver microsomes under hypoxic conditions (argon) generated predominantly the parent PA, riddellime. The reduction of riddelliine N-oxide to riddelliine was diminished, when the metabolism of riddelliine N-oxide with rat liver microsomes was conducted aerobically. Rat liver microsomal incubations of riddelliine N-oxide in the presence of calf thymus DNA produced a set of DHP-derived DNA adducts as detected and quantified by P-32-postlabeling/HPLC. The same DHP-derived DNA adducts were also found in liver DNA of F344 rats fed riddelliine N-oxide or riddelliine. When rats received doses of 1.0 mg/kg riddellime N-oxide for three consecutive days, the level of DNA adducts was 39.9 +/- 0.6 adducts/10(7) nucleotides, which was 2.6-fold less than that measured in rats treated with riddellime at the same dose. We have previously shown that these DHP-derived DNA adducts are produced by chronic feeding of riddellime and that the adduct levels correlated with liver tumor formation. Results presented in this paper indicate that riddellime N-oxide, through its conversion to riddellime, is also a potential genotoxic hepatocarcinogen. (C) 2003 Elsevier Ireland Ltd. All rights reserved.