Inhibitory effect of caffeic acid and its derivatives on human liver cytochrome P450 3A4 activity

Effects of caffeic acid (CAF) and its derivatives on human liver CYP3A4 activity were evaluated by using diazepam as a substrate. It was found that CAF inhibited CYP3A4 activity by uncompetitive inhibition with IC50 0.72 µM, whereas ester and amide analogues inhibited CYP3A4 by competitive inhibition with IC50 value of 0.31, 0.37, 0.46, 0.49, 0.53, 0.58, 0.75 and 0.82 µM for ethyl 1- (3’,4’-dihydroxyphenyl) propen amide (EDPA), phenmethyl 1- (3’,4’-dihydroxyphenyl) propen amide (PMDPA), phenethyl 1- (3’,4’-dihydroxyphenyl) propen amide (PEDPA), phenylethyl 1- (3’,4’-dihydroxyphenyl) propenate (PC), ethyl 1- (3’,4’-dihydroxyphenyl) propenate (EC), octyl 1- (3’,4’-dihydroxyphenyl) propen amide (ODPA), octyl 1- (3’,4’-dihydroxyphenyl) propenate (OC) and phenylmethyl 1- (3’,4’-dihydroxyphenyl) propenate (BC), respectively. The Ki values of CAF, PMDPA, EC, PC, ODPA, PEDPA, OC, EDPA and BC were 0.24, 0.29, 0.49, 0.56, 0.57, 0.59, 0.62, 0.62 and 1.03 µM, respectively. However, CAF and its derivatives had high potential to inhibit CYP3A4. Therefore, consumption of herbal medicine containing CAF and its derivatives that are concomitant with other medications should be cautiously monitored.   Key words: Cytochrome P450 3A4, caffeic acid, caffeic acid amide, caffeic acid ester.