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.

• Klíčová slova
• cytochrome P450 3A4, gene reporter assay, mRNA expression, precision-cut liver slices, pregnane X receptor, protein expression, sesquiterpene,
• MeSH
• aldo-keto reduktasy metabolismus   MeSH
• buňky Hep G2 MeSH
• cytochrom P-450 CYP3A metabolismus   MeSH
• farnesol farmakologie   MeSH
• hepatocyty metabolismus   MeSH
• játra enzymologie   MeSH
• karbonylreduktasa (NADPH) metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• messenger RNA metabolismus   MeSH
• metabolická clearance MeSH
• monocyklické seskviterpeny farmakologie   MeSH
• polycyklické seskviterpeny farmakologie   MeSH
• pregnanový X receptor agonisté   metabolismus   MeSH
• receptory aromatických uhlovodíků agonisté   metabolismus   MeSH
• rodina 2 cytochromů P450 metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• seskviterpeny farmakologie   MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aldo-keto reduktasy MeSH
• caryophyllene oxide MeSH Prohlížeč
• caryophyllene MeSH Prohlížeč
• cytochrom P-450 CYP3A MeSH
• cytochrome P-450 CYP2C subfamily MeSH Prohlížeč
• farnesol MeSH
• humulene MeSH Prohlížeč
• karbonylreduktasa (NADPH) MeSH
• messenger RNA MeSH
• monocyklické seskviterpeny MeSH
• nerolidol MeSH Prohlížeč
• polycyklické seskviterpeny MeSH
• pregnanový X receptor MeSH
• receptory aromatických uhlovodíků MeSH
• rodina 2 cytochromů P450 MeSH
• seskviterpeny MeSH
• systém (enzymů) cytochromů P-450 MeSH

β-caryophyllene oxide (CAO), α-humulene (HUM), trans-nerolidol (NER) and valencene (VAL) are constituents of the essential oil of Myrica rubra (MEO), which has significant antiproliferative effect in various cancer cell lines. In the present study, we compared the antiproliferative effect of these sesquiterpenes alone and in combination with the cytostatic drug doxorubicin (DOX) in cancer cell lines with different sensitivity to DOX. Two ovarian cancer cell lines (sensitive A2780 and partly resistant SKOV3) and two lymphoblast cancer cell lines (sensitive CCRF/CEM and completely resistant CEM/ADR) were used. The observed effects varied among sesquiterpenes and also differed in individual cell lines, with only VAL being effective in all the cell lines. A strong synergism of DOX with NER was found in the A2780 cells, while DOX acted synergistically with HUM and CAO in the SKOV3 cells. In the CCRF/CEM cells, a synergism of DOX with CAO and NER was observed. In resistant CEM/ADR cells, sesquiterpenes did not increase DOX efficacy, although they significantly increased accumulation of DOX (up to 10-times) and rhodamine-123 (substrate of efflux transporter ABCB1) within cancer cells. In conclusion, the tested sesquiterpenes were able to improve DOX efficacy in the sensitive and partly resistant cancer cells, but not in cells completely resistant to DOX.

• Klíčová slova
• ABCB1 transporter, Adriamycin, drug combinations, drug resistance, terpenes,
• MeSH
• akutní lymfatická leukemie farmakoterapie   MeSH
• doxorubicin farmakologie   terapeutické užití   MeSH
• kombinovaná farmakoterapie MeSH
• lidé MeSH
• mnohočetná léková rezistence účinky léků   MeSH
• monocyklické seskviterpeny MeSH
• Myrica chemie   MeSH
• nádorové buněčné linie MeSH
• oleje prchavé chemie   MeSH
• polycyklické seskviterpeny MeSH
• proliferace buněk účinky léků   MeSH
• seskviterpeny farmakologie   MeSH
• synergismus léků MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• caryophyllene oxide MeSH Prohlížeč
• doxorubicin MeSH
• humulene MeSH Prohlížeč
• monocyklické seskviterpeny MeSH
• nerolidol MeSH Prohlížeč
• oleje prchavé MeSH
• polycyklické seskviterpeny MeSH
• seskviterpeny MeSH
• valencene MeSH Prohlížeč

Sesquiterpenes, 15-carbon compounds formed from three isoprenoid units, are the main components of plant essential oils. Sesquiterpenes occur in human food, but they are principally taken as components of many folk medicines and dietary supplements. The aim of our study was to test and compare the potential inhibitory effect of acyclic sesquiterpenes, trans-nerolidol, cis-nerolidol and farnesol, on the activities of the main xenobiotic-metabolizing enzymes in rat and human liver in vitro. Rat and human subcellular fractions, relatively specific substrates, corresponding coenzymes and HPLC, spectrophotometric or spectrofluorometric analysis of product formation were used. The results showed significant inhibition of cytochromes P450 (namely CYP1A, CYP2B and CYP3A subfamilies) activities by all tested sesquiterpenes in rat as well as in human hepatic microsomes. On the other hand, all tested sesquiterpenes did not significantly affect the activities of carbonyl-reducing enzymes and conjugation enzymes. The results indicate that acyclic sesquiterpenes might affect CYP1A, CYP2B and CYP3A mediated metabolism of concurrently administered drugs and other xenobiotics. The possible drug-sesquiterpene interactions should be verified in in vivo experiments.

• Klíčová slova
• drug-metabolizing enzymes, farnesol, inhibition, nerolidol,
• MeSH
• farnesol chemie   farmakologie   MeSH
• inhibiční koncentrace 50 MeSH
• inhibitory cytochromu P450 chemie   farmakologie   MeSH
• játra enzymologie   MeSH
• kinetika MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• seskviterpeny chemie   farmakologie   MeSH
• subcelulární frakce enzymologie   MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• xenobiotika metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• farnesol MeSH
• inhibitory cytochromu P450 MeSH
• nerolidol MeSH Prohlížeč
• seskviterpeny MeSH
• systém (enzymů) cytochromů P-450 MeSH
• xenobiotika MeSH

The sesquiterpenes β-caryophyllene, β-caryophyllene oxide (CAO), α-humulene (HUM), trans-nerolidol (NER), and valencene (VAL) are substantial components of the essential oil from Myrica rubra leaves which has exhibited significant antiproliferative effects in several intestinal cancer cell lines, with CaCo-2 cells being the most sensitive. The present study was designed to evaluate the effects of these sesquiterpenes on the efficacy and toxicity of the anticancer drug doxorubicin (DOX) in CaCo-2 cancer cells and in primary culture of rat hepatocytes. Our results showed that HUM, NER, VAL and CAO inhibited proliferation of CaCo-2 cancer cells but they did not affect the viability of hepatocytes. CAO, NER and VAL synergistically potentiated the efficacy of DOX in cancer cells killing. All sesquiterpenes exhibited the ability to selectively increase DOX accumulation in cancer cells and did not affect DOX concentration in hepatocytes. Additionally, CAO and VAL were able to increase the pro-oxidative effect of DOX in CaCo-2 cells. Moreover, CAO mildly ameliorated DOX toxicity in hepatocytes. Based on all results, CAO seems to be the most promising compound for further testing.

• Klíčová slova
• Myrica rubra, antiproliferative effect, cytotoxicity, drugs combinations, terpenes,
• MeSH
• Caco-2 buňky MeSH
• doxorubicin farmakologie   toxicita   MeSH
• hepatocyty účinky léků   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• Myrica chemie   MeSH
• nádorové buněčné linie MeSH
• oxidace-redukce účinky léků   MeSH
• primární buněčná kultura MeSH
• protinádorové látky farmakologie   MeSH
• seskviterpeny farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• doxorubicin MeSH
• protinádorové látky MeSH
• seskviterpeny MeSH