Metabolic interactions of magnolol with cytochrome P450 enzymes: uncompetitive inhibition of CYP1A and competitive inhibition of CYP2C

Abstract

Magnolol (MAG; 5,5′-diallyl-2,2′-biphenyldiol) is a major bioactive component of Magnolia officinalis. We investigated the metabolic interactions of MAG with hepatic cytochrome P450 monooxygenase (CYP) through in vitro microsomal metabolism study using human (HLM) and rat liver microsomes (RLM). CYP2C and 3A subfamilies were significantly involved in the metabolism of MAG, while CYP1A subfamily was not in HLM and RLM. The relative contribution of phase I enzymes including CYP to the metabolism of MAG was comparable to that of uridine diphosphate glucuronosyltransferase (UGT) in RLM. Moreover, MAG potently inhibited the metabolic activity of CYP1A (IC₅₀ of 1.62 μM) and 2C (IC₅₀ of 5.56 μM), while weakly CYP3A (IC₅₀ of 35.0 μM) in HLM and RLM. By the construction of Dixon plot, the inhibition type of MAG on CYP activity in RLM was determined as follows: uncompetitive inhibitor for CYP1A (K_i of 1.09–12.0 μM); competitive inhibitor for CYP2C (K_i of 10.0–15.2 μM) and 3A (K_i of 93.7–183 μM). Based on the comparison of the current IC₅₀ and K_i values with a previously reported liver concentration (about 13 μM) of MAG after its seven times oral administration at a dose of 50 mg/kg in rats, it is suggested that MAG could show significant inhibition of CYP1A and 2C, but not CYP3A, in the in vivo rat system. These results could lead to further studies in clinically significant metabolism-mediated MAG–drug interactions.

• Cytochrome P450
• enzyme inhibition mechanism
• hepatic metabolism
• human liver microsome
• magnolol
• rat liver microsome

Declaration of interest

The authors report no declarations of interest. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (No. 2009-0083533) and the MarineBio Research Program (NRF-C1ABA001-2011-0018561).