In Vitro Inhibitory Effect of Isorhapontigenin on Cytochrome P450 Enzymes (CYP3A4, 2C9, and 2D6) and Its Characteristics

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ABSTRACT Isorhapontigenin is a polyphenol that is predominantly found in Gnetum cleistostachyum . It has been demonstrated to possess pharmacological effects, including anticancer and anti‐inflammatory properties. The objective was to examine the impact of isorhapontigenin on cytochrome P450 (CYP450) enzymes, thereby establishing a theoretical foundation for drug‐drug interactions and clinical prescriptions. The impact of isorhapontigenin (0, 2.5, 5, 10, 25, 50, and 100 µM) on CYP450 enzyme activity was investigated utilizing pooled human liver microsomes (HLMs). The activities of different CYP450 isozymes were assessed using the corresponding substrate and probe reactions with negative and positive controls (inhibitors). The inhibitory characteristics of isorhapontigenin on CYP450 isozymes were evaluated, and kinetic parameters were obtained via Lineweaver–Burk plots. Furthermore, the time‐dependent inhibitory effect of isorhapontigenin on CYP3A4 was also analyzed. Isorhapontigenin exhibited inhibitory effects on the activities of CYP3A4, 2C9, and 2D6 in a concentration‐dependent manner, with half‐maximal inhibitory concentration (IC 50 ) values of 16.08, 14.31, and 21.06 µM, respectively. Isorhapontigenin inhibited CYP3A4 in a non‐competitive manner ( K i = 8.40 µM). It was also a time‐based inhibitor of CYP3A4, exhibiting the K I and K inact values of 7.70 µM and 0.050 min −1 , respectively. The inhibition of CYP2C9 and 2D6 by isorhapontigenin was competitive, with K i values of 7.31 µM and 10.89 µM, respectively. The inhibitory effect of isorhapontigenin on CYP3A4, 2C9, and 2D6 activity was observed in vitro. These findings suggest that the inhibitory effect of isorhapontigenin on CYP450 enzymes may provide a theoretical basis for the co‐administration and drug development of this compound.

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