Inhibitory Effects of Cedrol, β-Cedrene, and Thujopsene on Cytochrome P450 Enzyme Activities in Human Liver Microsomes

Cedrol, beta-cedrene, and thujopsene are bioactive sesquiterpenes found in cedar essential oil and exert antiseptic, anti-inflammatory, antispasmodic, tonic, astringent, diuretic, sedative, insecticidal, and antifungal activities. These compounds are used globally in traditional medicine and cosmetics. The aim of this study was to investigate the inhibitory effects of cedrol, beta-cedrene, and thujopsene on the activities of eight major human cytochrome P-450 (CYP) enzymes using human liver microsomes to assess potential beta-cedrene-, cedrol-, and thujopsene-drug interactions. Cedrol, beta-cedrene, and thujopsene were found to be potent competitive inhibitors of CYP2B6-mediated bupropion hydroxylase with inhibition constant (K-i) values of 0.9, 1.6, and 0.8 mu M, respectively, comparable with that of a selective CYP2B6 inhibitor, thioTEPA (K-i, 2.9 mu M). Cedrol also markedly inhibited CYP3A4-mediated midazolam hydroxylation with a K-i value of 3.4 mu M, whereas beta-cedrene and thujopsene moderately blocked CYP3A4. Cedrol, beta-cedrene, and thujopsene at 100 mu M negligibly inhibited CYP1A2, CYP2A6, and CYP2D6 activities. Only thujopsene was found to be a mechanism-based inhibitor of CYP2C8, CYP2C9, and CYP2C19. Cedrol and thujopsene weakly inhibited CYP2C8, CYP2C9, and CYP2C19 activities, but beta-cedrene did not. These in vitro results indicate that cedrol, beta-cedrene, and thujopsene need to be examined for potential pharmacokinetic drug interactions in vivo due to their potent inhibition of CYP2B6 and CYP3A4.