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 PPAR? in Humans.

ABSTRACT: SCOPE:It is investigated whether at realistic dietary intake bixin and crocetin could induce peroxisome proliferator-activated receptor ? (PPAR?)-mediated gene expression in humans using a combined in vitro-in silico approach. METHODS AND RESULTS:Concentration-response curves obtained from in vitro PPAR?-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 PPAR?-mediated gene transcription in a concentration-dependent manner with similar potencies. Due to differences in kinetics, the predicted BMD50 values for in vivo PPAR? 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 PPAR? 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 PPAR?-mediated gene expression, without the need for a human intervention study.

SUBMITTER: Suparmi S 

PROVIDER: S-EPMC7003908 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature