Comprehensive Investigation of Stereoselective Food Drug Interaction Potential of Resveratrol on Nine P450 and Six UGT Isoforms in Human Liver Microsomes

• Published in: Pharmaceutics 2021-09, Vol.13 (9), p.1419
• Main Authors: Ji, Seung-Bae, Park, So-Young, Bae, Subin, Seo, Hyung-Ju, Kim, Sin-Eun, Lee, Gyung-Min, Wu, Zhexue, Liu, Kwang-Hyeon
• Format: Article
• Language: English
• Subjects: Analgesics; Cytochrome; cytochrome P450; Dietary supplements; Enzymes; food drug interactions; Nonsteroidal anti-inflammatory drugs; resveratrol; stereoselectivity; uridine 5′-diphosphoglucuronosyl transferase
• ISSN: 1999-4923; 1999-4923
• DOI: 10.3390/pharmaceutics13091419

The stereoselectivity of the food drug inhibition potential of resveratrol on cytochrome P450s and uridine 5′-diphosphoglucuronosyl transferases was investigated in human liver microsomes. Resveratrol enantiomers showed stereoselective inhibition of CYP2C9, CYP3A, and UGT1A1. The inhibitions of CYP1A2, CYP2B6, and CYP2C19 by resveratrol were stereo-nonselective. The estimated Ki values determined for CYP1A2 were 13.8 and 9.2 μM for trans- and cis-resveratrol, respectively. Trans-resveratrol noncompetitively inhibited CYP3A and UGT1A1 activities with Ki values of 23.8 and 27.4 μM, respectively. Trans-resveratrol inhibited CYP1A2, CYP2C19, CYP2E1, and CYP3A in a time-dependent manner with Ki shift values >2.0, while cis-resveratrol time-dependently inhibited CYP2C19 and CYP2E1. The time-dependent inhibition of trans-resveratrol against CYP3A4, CYP2E1, CYP2C19, and CYP1A2 was elucidated using glutathione as a trapping reagent. This information helped the prediction of food drug interaction potentials between resveratrol and co-administered drugs which are mainly metabolized by UGT1A1, CYP1A2, CYP2C19, CYP2E1, and CYP3A.