Citation

Jeong HU, Kwon SS, Kong TY, Kim JH, Lee HS. J. Toxicol. Environ. Health A 2014; 77: 1522-1532.

Copyright

(Copyright © 2014, Informa - Taylor and Francis Group)

DOI

10.1080/15287394.2014.955906

PMID

unavailable

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 M, respectively, comparable with that of a selective CYP2B6 inhibitor, thioTEPA (Ki, 2.9 M). Cedrol also markedly inhibited CYP3A4-mediated midazolam hydroxylation with a Ki value of 3.4 M, whereas β-cedrene and thujopsene moderately blocked CYP3A4. Cedrol, β-cedrene, and thujopsene at 100 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 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. © 2014 Taylor and Francis Group, LLC.

Language: en

Keywords

Humans; human; Drug Interactions; controlled study; high performance liquid chromatography; human cell; amfebutamone; unclassified drug; enzyme activity; cytochrome P450 3A4; cytochrome P450; midazolam; protein expression; metabolism; suicide substrate; drug interaction; Article; in vitro study; cytochrome P450 1A2; cytochrome P450 2D6; tandem mass spectrometry; Cytochrome P-450 Enzyme System; liver microsome; cytochrome P450 inhibitor; cytochrome P450 2C19; cytochrome P450 2C9; hydroxylation; enzymology; Sesquiterpenes; competitive inhibition; cytochrome P450 2B6; Microsomes, Liver; Terpenes; drug effects; beta cedrene; cedrene; cedrol; Cytochrome P-450 Enzyme Inhibitors; cytochrome P450 2A6; cytochrome P450 2C8; IC50; sesquiterpene; sesquiterpene derivative; terpene; thujopsene