Physiologically‐Based Kinetic Modeling Predicts Similar In Vivo Relative Potency of Senecionine N‐Oxide for Rat and Human at Realistic Low Exposure Levels. Issue 4 (24th January 2023)

• Record Type: Journal Article
• Authors: Widjaja, Frances; Alhejji, Yasser; Yangchen, Jamyang; Wesseling, Sebastiaan; Rietjens, Ivonne M. C. M.
• Is Part Of: Molecular nutrition & food research. Volume 67:Issue 4(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-01-24
• Subjects: human -- physiologically based kinetic (PBK) model -- rat -- relative potency (REP) value -- SEN -- SENO; Food -- Biotechnology -- Periodicals; Food -- Microbiology -- Periodicals; Nutrition -- Periodicals; Food -- Toxicology -- Periodicals; Nutrition -- Periodicals; Food Microbiology -- Periodicals; Food Technology -- Periodicals; Molecular Biology -- Periodicals; 664.0705
• DOI: 10.1002/mnfr.202200293
• Languages: English
• ISSNs: 1613-4125

Abstract

Abstract : Scope: This study aims to determine if previously developed physiologically‐based kinetic (PBK) model in rat can be modified for senecionine (SEN) and its N‐oxide (SENO), and be used to investigate potential species differences between rat and human in relative potency (REP) of the N‐oxide relative to the parent pyrrolizidine alkaloid (PA). Methods and results: In vitro derived kinetic parameters including the apparent maximum velocities ( V max ) and Michaelis–Menten constants ( K m ) for SENO reduction and SEN clearance are used to define the PBK models. The rat model is validated with published animal data, and the toxicokinetic profiles of SEN from either orally‐administered SENO or SEN are simulated. REP values of SENO relative to SEN amount to 0.84 and 0.89 in rat and human, respectively. Conclusion: The REP value can be dose‐ and species‐dependent, with the values for rat and human being comparable at low realistic exposure scenarios. In summary, PBK modeling serves as a valuable New Approach Methodology (NAM) tool for predicting REP values of PA‐N‐oxides and may actually result in more accurate REP values for human risk assessment than what would be defined using in vivo animal experiments. Abstract : The relative potency (REP) of senecionine N‐oxide to senecionine is dose‐ and species‐dependent. The dose dependency is of interest given that the values at low human dietary exposure levels cannot be determined in animal studies where high dose levels are used. Also, REP values for human can only be obtained with New Approach Methodology.