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

J Toxicol Environ Health A. 2014;77(22-24):1522-32. doi: 10.1080/15287394.2014.955906.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytochrome P-450 Enzyme Inhibitors / pharmacology
  • Cytochrome P-450 Enzyme System / metabolism*
  • Drug Interactions
  • Humans
  • Microsomes, Liver / drug effects*
  • Microsomes, Liver / enzymology*
  • Polycyclic Sesquiterpenes
  • Sesquiterpenes / pharmacology*
  • Terpenes / pharmacology*

Substances

  • Cytochrome P-450 Enzyme Inhibitors
  • Polycyclic Sesquiterpenes
  • Sesquiterpenes
  • Terpenes
  • cedrene
  • cedrol
  • Cytochrome P-450 Enzyme System
  • thujopsene