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
Louisse J., Spenkelink A., Beekmann K., Suparmi S., Rietjens I.M.C.M., de Haan L.
Abstract
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 (BMD<inf>50</inf>) 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 BMD<inf>50</inf> values for in vivo PPARγ activation are about 30-fold different, amounting to 115 and 3505 mg kg bw<sup>−1</sup> for crocetin and bixin, respectively. Human dietary and/or supplemental estimated daily intakes may reach these BMD<inf>50</inf> 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.
Daily oral administration of crocetin attenuates physical fatigue in human subjects
Ataka S., Ataka S., Kajimoto O., Kajimoto Y., Kuratsune H., Mizuma H., Mizuma H., Mizuno K., Mizuno K., Nozaki S., Nozaki S., Shirai T., Sugino T., Tahara T., Tahara T., Tanaka M., Tanaka M., Watanabe Y., Watanabe Y.
Intestinal formation of trans-crocetin from saffron extract (Crocus sativus L.) and in vitro permeation through intestinal and blood brain barrier
Brandt S., Dufer M., Galla H.J., Hensel A., Huwel S., Lautenschlager M., Riehemann K., Sendker J.
Dietary intake of carotenoids and risk of type 2 diabetes
Beulens J.W.J., Cadier E., Sluijs I., Spijkerman A.M.W., van der A D.L., van der Schouw Y.T.
Quantification of crocetin esters in saffron (Crocus sativus L.) using Raman spectroscopy and chemometrics
Alonso G.L., Anastasaki E.G., Carmona M., Kanakis C.D., Maggi L., Pappas C., Polissiou M.G., Zalacain A.
No Title
No Title
WHO
Annatto carotenoids attenuate oxidative stress and inflammatory response after high-calorie meal in healthy subjects
Conte L., da Silva D.T., de Carvalho J.A.M., Duarte T., Emanuelli T., Maurer L.H., Moresco R.N., Roehrs M., Somacal S.
Short-Term Bixin Supplementation of Healthy Subjects Decreases the Susceptibility of LDL to Cu 2+ -Induced Oxidation Ex Vivo
Conte L., Emanuelli T., Nichelle S.M., Rampelotto C., Robalo S.S., Roehrs M., Somacal S.
No Title
Abrahantes J.C., Aerts M., Benford D., Bodin L., Bottex B., Davis A., Edler L., Gundert-Remy U., Halldorsson T., Hardy A., Jeger M.J., Kass G., Knutsen K.H., Marques D.C., More S., Mortensen A., Naegeli H., Noteborn H., Ockleford C., Ricci A., Rychen G., Sand S., Schlatter J.R., Silano V., Slob W., Solecki R., Turck D.
In vitro-in vivo extrapolation: Estimation of human serum concentrations of chemicals equivalent to cytotoxic concentrations in vitro
Gulden M., Seibert H.
Vitale F., Colapietro A., Martellucci S., Mancini A., Alonso G.L., Gravina G.L., Mattei V., Llorens S., Angelucci A., Festuccia C.
International Journal of Molecular Sciences
Louisse J., Punt A., Wesseling S., Abdullah R., Spenkelink B., Rietjens I.M.C.M.
Journal of Applied Toxicology
Mendoza-De Gyves E., Di Consiglio E., Testai E., Pistollato F., Bal-Price A.
Reproductive Toxicology
Ramezan Y., Moradi D., Kamkari A., Tabrizi A.N., Lashkari A.
Food Science and Nutrition
Pierri C.L., Porcelli V., Laera L., Montaruli M., Sgobba M.N., Cafferati Beltrame L., Barile S., De Luca D.I., Scaglione V., Francavilla A.L., Todisco S., Volpicella M., Guerra L., De Grassi A.
Acta Pharmacologica Sinica
