Abstract
Sesquiterpenes, the main components of plant essential oils, are bioactive compounds with numerous health-beneficial activities. Sesquiterpenes can interact with concomitantly administered drugs due to the modulation of drug-metabolizing enzymes (DMEs). The aim of this study was to evaluate the modulatory effects of six sesquiterpenes (farnesol, cis-nerolidol, trans-nerolidol, α-humulene, β-caryophyllene, and caryophyllene oxide) on the expression of four phase I DMEs (cytochrome P450 3A4 and 2C, carbonyl reductase 1, and aldo-keto reductase 1C) at both the mRNA and protein levels. For this purpose, human precision-cut liver slices (PCLS) prepared from 10 patients and transfected HepG2 cells were used. Western blotting, quantitative real-time PCR and reporter gene assays were employed in the analyses. In the reporter gene assays, all sesquiterpenes significantly induced cytochrome P450 3A4 expression via pregnane X receptor interaction. However in PCLS, their effects on the expression of all the tested DMEs at the mRNA and protein levels were mild or none. High inter-individual variabilities in the basal levels as well as in modulatory efficacy of the tested sesquiterpenes were observed, indicating a high probability of marked differences in the effects of these compounds among the general population. Nevertheless, it seems unlikely that the studied sesquiterpenes would remarkably influence the bioavailability and efficacy of concomitantly administered drugs.
Highlights
In view of promoting healthier living as well as addressing various health issues, the tendency of the population to seek out and use herbal remedies and nutraceuticals has significantly increased over the past years [1]
precision-cut liver slices (PCLS) from 10 patients were incubated with sesquiterpenes, following which the changes in enzyme expression of CYP3A4, CYP2C, aldo-keto reductase 1C (AKR1C), and carbonyl reductase 1 (CBR1) were determined at the mRNA and protein levels
Three metabolites of farnesol have been identified in human liver microsomes [35]. If such metabolites of sesquiterpenes are less active in drug-metabolizing enzymes (DMEs) induction than parent compounds, higher effect of sesquiterpenes in some PCLS could be attributed to lower activity of CYP and/or UGT in those individuals
Summary
In view of promoting healthier living as well as addressing various health issues, the tendency of the population to seek out and use herbal remedies and nutraceuticals has significantly increased over the past years [1]. PCLS from 10 patients were incubated with sesquiterpenes, following which the changes in enzyme expression of CYP3A4, CYP2C, aldo-keto reductase 1C (AKR1C), and carbonyl reductase 1 (CBR1) were determined at the mRNA and protein levels. Three metabolites of farnesol (i.e., hydroxyfarnesol, farnesyl glucuronide and hydroxyfarnesyl glucuronide) have been identified in human liver microsomes [35] If such metabolites of sesquiterpenes are less active in DME induction than parent compounds, higher effect of sesquiterpenes in some PCLS could be attributed to lower activity of CYP and/or UGT in those individuals. Regulation of miRNA expression by several sesquiterpenes have been described [39,40], no report describing sesquiterpene-miRNA-PXR interaction was found
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