Bioactive constituents from ginger as human uridine-disphosphate glucuronosyltransferase 1A9 inhibitors: Potential metabolic modulators of mycophenolic acid.

Uridine-disphosphate glucuronosyltransferase 1A9 (UGT1A9) plays a critical role in the inactivation and detoxification of numerous exogenous drugs and endogenous molecules. Inhibition of UGT1A9 represents a promising strategy to enhance the exposure and efficacy of mycophenolic acid (MPA), a first-line immunosuppressive drug used in transplantation medicine. In this study, six natural molecules from ginger were identified as effective inhibitors of UGT1A9 through a high-throughput screening method. Notably, among all tested UGT isoforms, 6-shogaol, 8-shogaol, and 10-shogaol were found to be highly specific inhibitors of UGT1A9. Additionally, these six constituents from ginger could significantly reduce MPA metabolism, then effectively increase its exposure level, and prolong its half-life in living cells. More importantly, 6-shogaol not only inhibited MPA metabolism but also enhanced its efficacy in suppressing the proliferation of concanavalin A (ConA)-induced mouse primary splenic lymphocytes. Furthermore, 6-shogaol increased both systemic and tissue exposure, while also enhancing the hepatoprotective effects of MPA in a ConA-induced autoimmune hepatitis mouse model. Additionally, their underlying molecular mechanisms of UGT1A9 inhibition were elucidated through molecular docking and molecular dynamics simulations. Collectively, these results suggest that the six natural compounds in ginger exhibited promising potential to enhance the exposure level and immune efficacy of MPA by inhibiting UGT1A9.