Toxicokinetics of Riddelliine, a Carcinogenic Pyrrolizidine Alkaloid, and Metabolites in Rats and Mice

• Published in: Toxicology and applied pharmacology 2002-07, Vol.182 (2), p.98-104
• Main Authors: Williams, Lee, Chou, Ming W., Yan, Jian, Young, John F., Chan, Po C., Doerge, Daniel R.
• Format: Article
• Language: English
• Subjects: Animals; Area Under Curve; Biological and medical sciences; Biotransformation; Carcinogens - pharmacokinetics; Carcinogens - toxicity; Female; Half-Life; Male; mass spectrometry; Medical sciences; Mice; Plant poisons toxicology; pyrrolizidine alkaloid; Pyrrolizidine Alkaloids - chemistry; Pyrrolizidine Alkaloids - pharmacokinetics; Pyrrolizidine Alkaloids - therapeutic use; Pyrrolizidine Alkaloids - toxicity; Rats; Reproducibility of Results; riddelliine; Sex Characteristics; Spectrometry, Mass, Electrospray Ionization; toxicokinetics; Toxicology
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1006/taap.2002.9441

Riddelliine is a representative pyrrolizidine alkaloid, a class of naturally occurring toxic phytochemicals present in plant species worldwide. Human exposure to pyrrolizidine alkaloids occurs through consumption of herbal dietary supplements, including comfrey, and through contaminated livestock products (e.g., milk). A recently completed 2-year bioassay of riddelliine carcinogenicity showed that male and female rats and male mice, but not female mice, developed liver tumors. The toxicokinetics of riddelliine and two metabolites, the N-oxide and retronecine, were determined in serum following an oral gavage dose in male and female rats and mice using a validated liquid chromatography–electrospray mass spectrometric method. The results are consistent with extensive metabolism of riddelliine and its more polar metabolites prior to excretion. It is concluded that factors other than toxicokinetics are responsible for the observed species/sex specificity of gross toxicity or liver tumor induction in rats and mice.