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

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.
AuthorsNan Mei, Robert H Heflich, Ming W Chou, Tao Chen
JournalChemical research in toxicology (Chem Res Toxicol) Vol. 17 Issue 6 Pg. 814-8 (Jun 2004) ISSN: 0893-228X [Print] United States
PMID15206902 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Carcinogens
  • DNA Adducts
  • Pyrrolizidine Alkaloids
  • Transcription Factors
  • Viral Proteins
  • cII protein, bacteriophage lambda
  • riddelliine
Topics
  • Animals
  • Animals, Genetically Modified
  • Base Sequence (genetics)
  • Carcinogens (toxicity)
  • DNA Adducts
  • Dose-Response Relationship, Drug
  • Female
  • Liver (drug effects, metabolism)
  • Mutation (drug effects)
  • Pyrrolizidine Alkaloids (toxicity)
  • Rats
  • Transcription Factors (metabolism)
  • Viral Proteins

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