Combining In Vitro Data and Physiologically Based Kinetic Modeling Facilitates Reverse Dosimetry to Define In Vivo Dose–Response Curves for Bixin- and Crocetin-Induced Activation of PPARγ in Humans

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Scope: It is investigated whether at realistic dietary intake bixin and crocetin could induce peroxisome proliferator-activated receptor γ (PPARγ)-mediated gene expression in humans using a combined in vitro–in silico approach. Methods and results: Concentration–response curves obtained from in vitro PPARγ-reporter gene assays are converted to in vivo dose–response curves using physiologically based kinetic modeling-facilitated reverse dosimetry, from which the benchmark dose levels resulting in a 50% effect above background level (BMD50) are predicted and subsequently compared to dietary exposure levels. Bixin and crocetin activated PPARγ-mediated gene transcription in a concentration-dependent manner with similar potencies. Due to differences in kinetics, the predicted BMD50 values for in vivo PPARγ activation are about 30-fold different, amounting to 115 and 3505 mg kg bw−1 for crocetin and bixin, respectively. Human dietary and/or supplemental estimated daily intakes may reach these BMD50 values for crocetin but not for bixin, pointing at better possibilities for in vivo PPARγ activation by crocetin. Conclusion: Based on a combined in vitro–in silico approach, it is estimated whether at realistic dietary intakes plasma concentrations of bixin and crocetin are likely to reach concentrations that activate PPARγ-mediated gene expression, without the need for a human intervention study.

Original languageEnglish
Article number1900880
JournalMolecular Nutrition and Food Research
Issue number2
Publication statusPublished - Jan 2020



  • bixin
  • crocetin
  • peroxisome proliferator-activated receptor γ
  • physiologically based kinetic modeling
  • reverse dosimetry

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