Dietary Inhibitors of CYP3A4 Are Revealed Using Virtual Screening by Using a New Deep-Learning Classifier.

Yelena Guttman,Zohar Kerem

doi:10.1021/acs.jafc.2c00237

Yelena Guttman, Zohar Kerem

Open Access

https://doi.org/10.1021/acs.jafc.2c00237

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Abstract

CYP3A4 is the main human enzyme responsible for phase I metabolism of dietary compounds, prescribed drugs and xenobiotics, steroid hormones, and bile acids. The inhibition of CYP3A4 activity might impair physiological mechanisms, including the endocrine system and response to drug admission. Here, we aimed to discover new CYP3A4 inhibitors from food and dietary supplements. A deep-learning model was built that classifies compounds as either an inhibitor or noninhibitor, with a high specificity of 0.997. We used this classifier to virtually screen ∼60,000 dietary compounds. Of the 115 identified potential inhibitors, only 31 were previously suggested. Many herbals, as predicted here, might cause impaired metabolism of drugs, and endogenous hormones and bile acids. Additionally, by applying Lipinski’s rules of five, 17 compounds were also classified as potential intestine local inhibitors. New CYP3A4 inhibitors predicted by the model, bilobetin and picropodophyllin, were assayed in vitro.

Highlights

Accumulated evidence points to the potent inhibition of cytochrome P450 3A4 (CYP3A4) by dietary phytochemicals, many of which are consumed as spices, dietary supplements, and herbal supplements.[1]
CYP3A4 is the main enzyme involved in the phase I metabolism of a wide range of endogenous compounds, i.e., steroid hormones, lipids, and bile acids, as well as xenobiotics, including dietary compounds and over 50% of prescribed drugs
The inhibition of CYP3A4 might cause various physiological consequences, such as cholestasis, a condition characterized by accumulation of toxic bile acids, impairment of the endocrine system signaling, and an increased risk of drug toxicity.[2−4] deliberate inhibition of CYP3A4-mediated drug metabolism is sometimes utilized to increase the oral bioavailability of certain medications previously administered intravenously.[5]

Summary

Introduction

Accumulated evidence points to the potent inhibition of cytochrome P450 3A4 (CYP3A4) by dietary phytochemicals, many of which are consumed as spices, dietary supplements, and herbal supplements.[1]. The human CYP3A4 is recognized to be as active in the small intestine as it is in the liver. It accounts for approximately 80% of the total intestinal P450 content and represents the principal intestinal drug-metabolizing system in humans. The total amount of CYP3A expressed in the human small intestine represents approximately only 1% of the amount expressed in the liver, the substantial intestinal metabolism is due to prolonged exposure times.[6] The predominance of CYP3A4 in the human intestine enables it to act several-fold more efficiently in the intestine than in the liver.[7]

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