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. 2004 Jun;17(6):814-8.
doi: 10.1021/tx049955b.

Mutations induced by the carcinogenic pyrrolizidine alkaloid riddelliine in the liver cII gene of transgenic big blue rats

Nan Mei  1 , Robert H Heflich, Ming W Chou, Tao Chen
Affiliations

Mutations induced by the carcinogenic pyrrolizidine alkaloid riddelliine in the liver cII gene of transgenic big blue rats

Nan Mei et al. Chem Res Toxicol. 2004 Jun.

Abstract

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.

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Figures

Figure 1.
Figure 1.
Riddelliine-induced cII MF as a function of dose. Big Blue rats were gavaged with 0.1–1.0 mg/kg body weight riddelliine for 12 weeks, and the cII MF was determined in the liver 1 day after the last treatment. The induced MF was obtained by subtracting the background MF observed in the vehicle control rats. The data represent the mean ± SD for each group of six rats.
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