Mechanism-based inhibition of CYP3A4 by constituents of Zingiber aromaticum

Abstract

Sixteen compounds isolated from Zingiber aromaticum and showing concentration-dependent inhibition with IC 50 values less than 100 μm, were analyzed for their possibility of time-, concentration-, and NADPH-dependent inhibition of CYP3A4 and four were analyzed for CYP2D6. All seven kaempferol glycosides and two kaempferol derivatives (4, 5, 8-14) appear to be the mechanism-based inhibitors of CYP3A4 enzyme in which the inhibition is irreversible and driven by the catalytic process. The other compounds showed no NADPH-dependent inhibition or reversible inhibition, and thus do not appear to be mechanism-based inhibitors. K 1 values for compounds 4, 5, 8-14 were in the range of 2.21-27.01 μM, whereas the k inact values were 0.23-0.65 min -1. Kaempferol-3-O-(2,3,4-tri-O-acetyl-α-L- rhamnopyranoside) (5) was found to be the most potent CYP3A4 inactivator with K 1, and k inact values of 2.21 μM and 0.45 min -1, respectively. © 2005 Pharmaceutical Society of Japan.