Inhibition of aflatoxins on UDP-glucuronosyltransferases (UGTs)

Aflatoxins have been recognized as the most harmful mycotoxins leading to various toxic effects. The present study aims to determine the inhibition behavior of aflatoxins on the activity of the important phase II metabolizing enzymes, UDP-glucuronosyltransferases (UGTs), based on in vitro incubation system of recombinant human UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4-MU). 100 μM AFB1 and AFG1 exhibited extensive inhibition towards UGT isoforms especially UGT1A7 and UGT1A8, with the inhibition ratios to be 71.38%, 72.95% and 72.79% for AFB1 to UGT1A7, AFB1 to UGT1A8 and AFG1 to UGT1A8, respectively. Molecular docking results showed that hydrogen bonds and hydrophobic contacts of the particular structure consisting of double furan ring with double bond contributed to the interaction of aflatoxins and UGTs. Kinetics analysis, including inhibition types and kinetics parameters (K_i), and in vitro-in vivo extrapolation (IVIVE) indicated that there might be a medium possibility of inhibition on UGTs by aflatoxins in vivo. In conclusion, the present study indicated that aflatoxins could possibly disturb endogenous metabolism by inhibiting the activity of UGTs so as to exhibit toxic effects.