Phloretin exhibits potential food-drug interactions by inhibiting human UDP-glucuronosyltransferases in vitro

Jinqian Chen; Hao Zhang; Xia Hu; Mengyuan Xu; Yanjun Su; Chunze Zhang; Yuan Yue; Xiaomin Zhang; Xinyu Wang; Wei Cui; Zhenyu Zhao; Xichuan Li

doi:10.1016/j.tiv.2022.105447

Phloretin exhibits potential food-drug interactions by inhibiting human UDP-glucuronosyltransferases in vitro

Toxicol In Vitro. 2022 Oct:84:105447. doi: 10.1016/j.tiv.2022.105447. Epub 2022 Jul 19.

Authors

Jinqian Chen¹, Hao Zhang², Xia Hu³, Mengyuan Xu², Yanjun Su⁴, Chunze Zhang⁵, Yuan Yue², Xiaomin Zhang², Xinyu Wang², Wei Cui⁶, Zhenyu Zhao⁷, Xichuan Li⁸

Affiliations

¹ Departments of Pharmacy, NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital, Tianjin 300134, PR China.
² Tianjin Key Laboratory of Animal and Plant Resistance, College of Life Sciences, Tianjin Normal University, Tianjin 300387, PR China.
³ Department of Agriculture Insect, Institute of Plant Protection, Tianjin Academy of Agricultural Sciences, Tianjin 300384, PR China.
⁴ Department of Lung Cancer, Tianjin Lung Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, PR China.
⁵ Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, PR China.
⁶ School of Mathematical Sciences and LPMC, Nankai University, Tianjin 300070, PR China.
⁷ Departments of Pharmacy, NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital, Tianjin 300134, PR China. Electronic address: zhaozhenyu0858@163.com.
⁸ Tianjin Key Laboratory of Animal and Plant Resistance, College of Life Sciences, Tianjin Normal University, Tianjin 300387, PR China. Electronic address: xichuanli@tjnu.edu.cn.

PMID: 35868516
DOI: 10.1016/j.tiv.2022.105447

Abstract

Phloretin is a well-known apple polyphenol possessing a wide variety of biological effects and has been widely used in many fields. However, it's unclear whether phloretin has an effect on the activity of human UGT enzymes. Our study indicated that phloretin inhibited human UGTs on a broad spectrum. Further kinetic analysis revealed that phloretin inhibited UGT1A1, 1A6, 1A9, 2B7, and 2B15 in a noncompetitive manner, with calculated K_i of 8.34 μM, 16.69 μM, 10.58 μM, 17.74 μM and 2.46μΜ, respectively, whereas phloretin inhibited UGT1A7 in an un-competitive manner, with calculated K_i of 5.70 μM. According to the quantitative risk prediction, co-administration of phloretin with drugs primarily metabolized by UGT1A7 and/or UGT2B15 may result in potential food-drug interactions. To sum up, when phloretin or phloretin-rich food is administered with medications metabolized by UGT1A7 and/or UGT2B15, concern should be exercised.

Keywords: Apple polyphenols; Enzymes inhibition; Food-drug interactions; IVIVE; Phloretin; UGTs.

MeSH terms

Food-Drug Interactions*
Glucuronosyltransferase / metabolism
Humans
Kinetics
Phloretin* / pharmacology
Uridine Diphosphate

Substances

Uridine Diphosphate
Glucuronosyltransferase
Phloretin