In Vitro Inhibitory Effects of Esculetin on Human Liver Cytochrome P450 Enzymes

Esculetin (ESC), a derivative of coumarin, possesses a number of pharmacological activities. Cytochrome P450 (CYP) enzymes play a vital role in the biotransformation of xenobiotics; its activity directly affects the bioavailability of the drugs. Therefore, should be paid attention in the effect of ESC on the activity of CYPs. The effects of ESC on eight human liver CYP isoforms (i.e., 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19 and 2C8) were investigated in vitro using human liver microsomes (HLMs), and the enzyme kinetic parameters were calculated. ESC inhibited the activity of CYP3A4, CYP2E1 and CYP1A2, with IC50 values of 15.01, 23.22 and 19.42 mu M, respectively, but other CYPs were not affected. The inhibition of CYP3A4 by ESC was best fitted in a non-competitive manner, with the Ki value of 7.53 mu M. Whereas, ESC competitively inhibited the activity of CYP2E1 and CYP1A2, with Ki values of 11.13 and 9.19 mu M, respectively. In addition, ESC is a time dependent inhibitor for CYP3A4 with K-I/K-inact value of 9.52/0.061 min(-1)mu M-1. The in vitro studies of ESC with CYP isoforms indicate that ESC has the potential to cause pharmacokinetic drug interactions with other co-administered drugs metabolized by CYP3A4, CYP2E1 and CYP1A2. Further clinical studies are needed to evaluate the significance of this interaction.