Author:
Widjaja Frances,Zheng Liang,Wesseling Sebastiaan,Rietjens Ivonne M. C. M.
Abstract
Over 1,000 pyrrolizidine alkaloids (PAs) and their N-oxides (PA-N-oxides) occur in 3% of all flowering plants. PA-N-oxides are toxic when reduced to their parent PAs, which are bioactivated into pyrrole intermediates that generate protein- and DNA-adducts resulting in liver toxicity and carcinogenicity. Literature data for senecionine N-oxide in rats indicate that the relative potency (REP) value of this PA-N-oxide compared to its parent PA senecionine varies with the endpoint used. The first endpoint was the ratio between the area under the concentration-time curve (AUC) for senecionine upon dosing senecionine N-oxide or an equimolar dose of senecionine, while the second endpoint was the ratio between the amount for pyrrole-protein adducts formed under these conditions. This study aimed to investigate the mode of action underlying this endpoint dependent REP value for senecionine N-oxide with physiologically based kinetic (PBK) modeling. Results obtained reveal that limitation of 7-GS-DHP adduct formation due to GSH depletion, resulting in increased pyrrole-protein adduct formation, occurs more likely upon high dose oral PA administration than upon an equimolar dose of PA-N-oxide. At high dose levels, this results in a lower REP value when based on pyrrole-protein adduct levels than when based on PA concentrations. At low dose levels, the difference no longer exists. Altogether, the results of the study show how the REP value for senecionine N-oxide depends on dose and endpoint used, and that PBK modeling provides a way to characterize REP values for PA-N-oxides at realistic low dietary exposure levels, thus reducing the need for animal experiments.
Funder
China Scholarship Council
Subject
Pharmacology (medical),Pharmacology
Reference36 articles.
1. Relative potency of fifteen pyrrolizidine alkaloids to induce DNA damage as measured by micronucleus induction in HepaRG human liver cells;Allemang;Food Chem. Toxicol.,2018
2. Bioassay of lasiocarpine for possible carcinogenicity;Bioassay;Natl. Cancer Inst. Carcinog. Tech. Rep. Ser.,1978
3. NTP technical report on toxicology and carcinogenesis studies of riddelliine. F344/N rats and B6C3F1 mice;Chan;NTP Tr.,2001
4. Intracellular glutathione plays important roles in pyrrolizidine alkaloids-induced growth inhibition on hepatocytes;Chen;Environ. Toxicol. Pharmacol.,2009
5. Hepatic sinusoidal-obstruction syndrome: Toxicity of pyrrolizidine alkaloids;Chojkier;J. Hepatol.,2003
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