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.

Essential oil components and cytochrome P450 enzymes: a review

“…It is important to note, however, that the inhibition of CYP2B6 and CYP3A4 activity in vitro does not necessarily translate into drug–drug interactions in clinical situations. To predict any possible drug–drug interaction potential of cedrol, β‐cedrene, and thujopsene, pharmacokinetic studies of these components and in vivo studies are required to determine the clinical relevance of CYP2B6 and CYP3A4 inhibition …”

“…To predict any possible drug-drug interaction potential of cedrol, β-cedrene, and thujopsene, pharmacokinetic studies of these components and in vivo studies are required to determine the clinical relevance of CYP2B6 and CYP3A4 inhibition. 56…”

Bioactivity and chemical profiling of the Juniperus excelsa, which support its usage as a food preservative and nutraceutical

“…As an example, α-pinene and cedrol-rich oil could be effectively used as a local antiseptic. [32] Moreover, J. excelsa oils could be used as naturally derived preservatives due to the limonene-rich content. Namely, limonene is capable of reducing microbial contamination and preventing food spoilage in a wide range of food, but without adversely altering the taste or function.…”

From Weed to Medicinal Plant: Antioxidant Capacities and Phytochemicals of Various Extracts of Mikania micrantha

“…For instance, caryophyllene, one of the bicyclic sesquiterpenes has potential antioxidant, anti-inflammatory, and antimicrobial activities (Sharma et al, 2016). Another compounds such as cedrol (a sesquiterpene alcohol), cedrene, and thujopsene possess inhibitory effects against cytochrome P450 (CYP) enzyme (CYP2B6 and CYP3A4) in human liver microsomes in vitro as well as anti-inflammatory, antifungal, insecticidal, diuretic, antispasmodic, astringent, sedative and antiseptic properties (Jeong et al, 2014). All phytochemicals detected in the ethyl acetate extracts of M. micrantha in present study was reported for the first time, except α-Longipinene, β-Himachalene, β-Cubebene, and α-Zingiberene, which were also reported in the previous study of the essential oil composition of M. micrantha from China (Zhang et al, 2004).…”