The inhibition of UDP-glucuronosyltransferases (UGTs) by vitamin A

Abstract

1. The exposed level of vitamin A in plasma might be exceeded due to the both inadvertent and clinical utilization. The adverse effects of vitamin A have been frequently reported, however, the mechanism remains unclear. The inhibition of vitamin A on the activity of UDP-glucuronosyltransferases (UGTs) was determined using in vitro incubation system to explain the adverse effects of vitamin A from a new perspective.

2. UGT supersomes catalyzed glucuronidation of 4-methylumbelliferone (4-MU), trifluoperazine (TFP), and cotinine was used as the probe reaction to evaluate the inhibition of vitamin A toward UGT isoforms, and 100 μM of vitamin A significantly inhibited the activity of all the tested UGT isoforms. Vitamin A exerted competitive inhibition on the activity of UGT1A1, 2B4, 2B7, and 2B15, and the inhibition kinetic parameters (K_i) were calculated to be 31.1, 16.8, 2.2, and 11.6 μM for UGT1A1, 2B4, 2B7, and 2B15. In silico docking method was used to try to elucidate the inhibition mechanism of vitamin A toward UGT2B7. The results showed the significant contribution of hydrogen bonds and hydrophobic interaction on the UGT2B7 inhibition by vitamin A.

3. The present study provides a new perspective for the adverse effects of vitamin A through reporting the inhibition of vitamin A on the activity of important phase II drug-metabolizing enzymes UGTs, which benefits our deep understanding of mechanism of vitamin A's adverse effects when high exposure of vitamin A occurs.

• Enzyme inhibition
• UDP-glucuronosyltransferases (UGTs)
• vitamin A

Declaration of interest

This work was supported by National Natural Science Foundation of China (No. 81503151, 81303146), the project for individualized diagnosis and treatment of colorectal cancer (No. LNCCC-B05-2015), Supported by China Postdoctoral Science Foundation (2016M590210), Foundation of Committee on Science and Technology of Tianjin (Grant No. 15JCYBJC54700), and Tianjin Project of Thousand Youth Talents.