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

• Main Authors: Seung-Bae Ji (Author), So-Young Park (Author), Subin Bae (Author), Hyung-Ju Seo (Author), Sin-Eun Kim (Author), Gyung-Min Lee (Author), Zhexue Wu (Author), Kwang-Hyeon Liu (Author)
• Format: Book
• Published: MDPI AG, 2021-09-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/pharmaceutics13091419; 1999-4923
• Keywords: cytochrome P450; food drug interactions; resveratrol; stereoselectivity; uridine 5'-diphosphoglucuronosyl transferase; Pharmacy and materia medica; RS1-441
• Source: Pharmaceutics, Vol 13, Iss 9, p 1419 (2021)

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 <i>K</i>_i values determined for CYP1A2 were 13.8 and 9.2 μM for <i>trans</i>- and <i>cis</i>-resveratrol, respectively. <i>Trans</i>-resveratrol noncompetitively inhibited CYP3A and UGT1A1 activities with <i>K</i>_i values of 23.8 and 27.4 μM, respectively. <i>Trans</i>-resveratrol inhibited CYP1A2, CYP2C19, CYP2E1, and CYP3A in a time-dependent manner with <i>K</i>_i shift values >2.0, while <i>cis</i>-resveratrol time-dependently inhibited CYP2C19 and CYP2E1. The time-dependent inhibition of <i>trans</i>-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.