Riddelliine is a naturally occurring
pyrrolizidine alkaloid that forms a number of different mononucleotide and dinucleotide adducts in
DNA. It is a rodent
carcinogen and a potential human hazard via food contamination. To examine the mutagenicity of
riddelliine, groups of six female transgenic Big Blue rats were gavaged with 0.1, 0.3, and 1.0 mg
riddelliine per kg
body weight. The middle and high doses resulted in liver
tumors in a previous
carcinogenesis bioassay. The animals were treated 5 days a week for 12 weeks and sacrificed 1 day after the last treatment. The liver
DNA was isolated for analysis of the mutant frequency (MF) in the transgenic cII gene, and the types of mutations were characterized by sequencing the mutants. A significant dose-dependent increase in MF was found, increasing from 30 x 10(-)(6) in the control animals to 47, 55, and 103 x 10(-)(6) in the low, middle, and high dose groups, respectively. Molecular analysis of the mutants indicated that there was a statistically significant difference between the mutational spectra from the
riddelliine-treated and the control rats. A G:C --> T:A transversion (35%) was the major type of mutation in rats treated with
riddelliine, whereas a G:C --> A:T transition (55%) was the predominant mutation in the controls. In addition, mutations from the
riddelliine-treated rats included an unusually high frequency (8%) of tandem base substitutions of GG --> TT and GG --> AT. These results indicate that
riddelliine is a genotoxic
carcinogen in rat liver and that the types of mutations induced by
riddelliine are consistent with
riddelliine adducts involving G:C base pairs.