Comparison of the Inhibition Capability of Rhynchophylline and Isorhynchophylline towards UDP-Glucuronosyltransferase (UGT) 1A6

Rhynchophylline and isorhynchophylline are two compounds isolated from Uncaria rhynchophylla, and have been reported to exert various biochemical and pharmacological activities. The present study aims to determine the influence of these two compounds towards important phase II drug-metabolizing enzyme (DME) UDP-glucuronosyltransferase (UGT) 1A6. 100 mu M of rhynchophylline and isorhynchophylline showed significant inhibition towards the activity of UGT1A6 (p < 0.001). Compared with rhynchophylline, isorhynchophylline exerted stronger inhibition towards UGT1A6. Interesting results were found when determining the influence of multiple concentration of rhynchophylline and isorhynchophylline towards UGT1A6. Under 20 mu M of rhynchophylline or isorhynchophylline, the activity of UGT1A6 was activated. Rhynchophylline or isorhynchophylline inhibited the activity of UGT1A6 in a concentration-dependent behavior when the concentration was above 20 mu M. Furthermore, the inhibition kinetic determination was carried out through Lineweaver-Burk plots. The intersection point for all the lines in the Lineweaver-Burk plot was located in the vertical axis, indicating the competitive inhibition of rhynchophylline towards UGT1A6. For the inhibition of isorhynchophylline towards UGT1A6, the intersection point for all the lines in the Lineweaver-Burk plot was located in the horizontal axis, indicating the noncompetitive inhibition of isorhynchophylline towards UGT1A6. Through the nonlinear fitting and linear fitting for rhynchophylline and isorhynchophylline respectively, the inhibition kinetic parameters (Ki) were calculated to be 60.3 mu M for rhynchophylline and 21.8 mu M for isorhynchophylline. In conclusion, the inhibition of rhynchophylline and isorhynchophylline towards UGT1A6 was investigated in the present study. Different inhibition type was observed for the inhibition of rhynchophylline and isorhynchophylline towards UGT1A6, and stronger inhibition of isorhynchophylline than rhynchophylline was also detected.