title: Inhibitory effects of cedrol, β-cedrene, and thujopsene on cytochrome P450 enzyme activities in human liver microsomes.
abstract: Cedrol, β-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, β-cedrene, and thujopsene on the activities of eight major human cytochrome P-450 (CYP) enzymes using human liver microsomes to assess potential β-cedrene-, cedrol-, and thujopsene-drug interactions. Cedrol, β-cedrene, and thujopsene were found to be potent competitive inhibitors of CYP2B6-mediated bupropion hydroxylase with inhibition constant (Ki) values of 0.9, 1.6, and 0.8 μM, respectively, comparable with that of a selective CYP2B6 inhibitor, thioTEPA (Ki, 2.9 μM). Cedrol also markedly inhibited CYP3A4-mediated midazolam hydroxylation with a Ki value of 3.4 μM, whereas β-cedrene and thujopsene moderately blocked CYP3A4. Cedrol, β-cedrene, and thujopsene at 100 μM 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 β-cedrene did not. These in vitro results indicate that cedrol, β-cedrene, and thujopsene need to be examined for potential pharmacokinetic drug interactions in vivo due to their potent inhibition of CYP2B6 and CYP3A4.
authors.affiliation: a Drug Metabolism & Bioanalysis Laboratory, College of Pharmacy , The Catholic University of Korea , Bucheon , Korea.
authors.forename: Hyeon-Uk
authors.initials: HU
authors.lastname: Jeong
authors.forename: Soon-Sang
authors.initials: SS
authors.lastname: Kwon
authors.forename: Tae Yeon
authors.initials: TY
authors.lastname: Kong
authors.forename: Ju Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Hye Suk
authors.initials: HS
authors.lastname: Lee
mesh_terms: D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology*; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes / Q000494:pharmacology*; D013729:Terpenes / Q000494:pharmacology*
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes; D013729:Terpenes; C000393:cedrene; C078669:cedrol; D003577:Cytochrome P-450 Enzyme System; C433908:thujopsene