Inhibition of cytochrome P450 3A by acetoxylated analogues of resveratrol in in vitro and in silico models.

Loai Basheer,Zohar Kerem,Keren Schultz

doi:10.1038/srep31557

Loai Basheer, Zohar Kerem + Show 1 more

Open Access

https://doi.org/10.1038/srep31557

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Journal: Scientific reports	Publication Date: Aug 17, 2016
Citations: 13	License type: CC BY 4.0

Affiliation: Hebrew University of Jerusalem

Abstract

Many dietary compounds, including resveratrol, are potent inhibitors of CYP3A4. Here we examined the potential to predict inhibition capacity of dietary polyphenolics using an in silico and in vitro approaches and synthetic model compounds. Mono, di, and tri-acetoxy resveratrol were synthesized, a cell line of human intestine origin and microsomes from rat liver served to determine their in vitro inhibition of CYP3A4, and compared to that of resveratrol. Docking simulation served to predict the affinity of the synthetic model compounds to the enzyme. Modelling of the enzyme’s binding site revealed three types of interaction: hydrophobic, electrostatic and H-bonding. The simulation revealed that each of the examined acetylations of resveratrol led to the loss of important interactions of all types. Tri-acetoxy resveratrol was the weakest inhibitor in vitro despite being the more lipophilic and having the highest affinity for the binding site. The simulation demonstrated exclusion of all interactions between tri-acetoxy resveratrol and the heme due to distal binding, highlighting the complexity of the CYP3A4 binding site, which may allow simultaneous accommodation of two molecules. Finally, the use of computational modelling may serve as a quick predictive tool to identify potential harmful interactions between dietary compounds and prescribed drugs.

Highlights

T-Resveratrol is a polyphenol found in grape skin and red wine
The inhibitory effects of t-resveratrol on CYP3A4, both in vitro and in vivo, are well documented in the literature[15,16,17,18,19,37] and clinical trials have found that the administration of resveratrol increases plasma concentrations of several drugs[20,27]
Several QSAR and pharmacophore mapping studies point to the importance of lipophilicity, and to the role of hydrogen bond (H-bond) in determining how various molecules interact with CYP3A428,29,31,33

Summary

Introduction

T-Resveratrol (trans-3,5,4′-trihydroxystilbene) is a polyphenol found in grape skin and red wine. The importance of potential hydrogen bonding in determining the nature of interactions with CYP3A4 has been proposed in previous works[14,31,32,33,34]. In the present work, using the predicted docking energy, we have designed novel acetoxy-stilbenes (Fig. 1), in an effort to identify structural determinants that increase the inhibition of CYP3A4, through an increase in either lipophilicity or the addition of H-bond acceptors. Previous works have suggested a high structural similarity between the human CYP3A4 and the isozymes CYP3A1 and CYP3A2 which are expressed predominantly in the rat liver[38]. Using two in vitro models presenting different isozymes of CYP3A, i.e., human CYP3A4 in Caco2/TC7 cell culture, and CYP3A in rat liver microsomes (RLM), and an in silico docking model allowed us to define structural components required for a compound to potently inhibit CYP3A4

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Conclusion