Inhibitory effects of Kratom constituents, mitragynine and 7-hydroxymitragynine, on 4-methylumbelliferone glucuronidation by human UDP-glucuronosyltransferases

Abstract

As Kratom use increases, concerns about potential herb-drug interactions with liver enzymes, particularly UDP-glucuronosyltransferases (UGTs), have emerged. This study investigated the inhibitory effects of Kratom leaf constituents, mitragynine and 7-hydroxymitragynine, on 4-methylumbelliferone (4MU) glucuronidation by a panel of recombinant human UGT enzymes, including UGT1A1, UGT1A3, UGT1A6, UGT1A9, UGT2B7, and UGT2B15. The degree of inhibition exhibited by mitragynine and 7-hydroxymitragynine on UGTs varied. Mitragynine exhibited the highest inhibitory potency on UGT1A3 with an IC ₅₀ value of 72 µM. Moderate inhibition potency of mitragynine were observed for UGT1A6, UGT1A9 and UGT2B15, with IC ₅₀ value of 121, 131, and 152 µM, respectively, whereas the inhibition on UGT1A1 and UGT2B7 was low (IC ₅₀ > 200 µM). 7-Hydroxymitragynine exhibited the highest inhibitory potency on UGT1A9, with IC ₅₀ value of 51 µM, while moderate potency was observed for UGT1A1 and UGT1A3, with IC ₅₀ value of 196 and 141 µM, respectively. The inhibitory potency of 7-hydroxymitragynine on UGT2B15 was low (IC ₅₀ > 200 µM), while negligible effects were observed for UGT1A6 and UGT2B7. Kinetic inhibition study revealed that mitragynine noncompetitively inhibited UGT1A3 (K _i = 45 µM) and competitively inhibited UGT1A9 (K _i = 114 µM), while 7-hydroxymitragynine competitively inhibited UGT1A3 (K _i = 33 µM) and noncompetitively inhibited UGT1A9 (K _i = 29 µM). The experimental K _i values found here are relatively high compared to the maximum plasma concentrations of mitragynine and 7-hydroxymitragynine reported in humans, suggesting an unlikely potential for herb-drug interactions via UGT inhibition.

Graphical Abstract

Highlights

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  As Kratom use rises, concerns grow about its potential herb-drug interactions with UGTs.

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  The inhibition degree by mitragynine and 7-hydroxymitragynine on UGTs varied.

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  Mitragynine showed potential in vitro inhibition on UGT1A3, and 7-hydroxymitragynine on UGT1A9.