Constituents of Indonesian Medicinal Plant Averrhoa bilimbi and Their Cytochrome P450 3A4 and 2D6 Inhibitory Activities

Abstract

As constituents of Averrhoa bilimbi leaves we identified three new compounds (1-3) together with 12 known ones (4-15); their inhibitory activities on cytochrome P450 3A4 (CYP3A4) and 2D6 (CYP2D6) were examined. Among the isolated compounds, the mixture of 1 and 2, and compounds 4 and 9 showed strong inhibition on CYP3A4, but mild or no inhibition on CYP2D6. These compounds revealed the characteristics of 1) time- and concentration-dependent inhibition, 2) requirement of NADPH for the inhibition, 3) no protection by nucleophiles, and 4) suppression of the inhibition by competitive inhibitor. Thus, they are suggested to be mechanism-based inactivators of CYP3A4 and CYP2D6. The kinetic parameters for the inactivation (kinact and KI) were 0.19 min–1 and 36.7 μM for the mixture of 1 and 2, 0.126 min–1 and 10.5 μM for 4, and 0.29 min–1 and 23.4 μM for 9.