The inhibitory effects of β-Caryophyllene, β-Caryophyllene oxide and α-Humulene on the activities of the main drug-metabolizing enzymes in rat and human liver in vitro
Abstract
Sesquiterpenes, the main components of plant essential oils, are often taken in the form of folk medicines and dietary supplements. Several sesquiterpenes possess interesting biological activities but they could interact with concurrently administered drugs via inhibition of drug-metabolizing enzymes. Therefore, the present study was designed to test the potential inhibitory effect of tree structurally relative sesquiterpenes β-caryophyllene (CAR), β-caryophyllene oxide (CAO) and α-humulene (HUM) on the activities of the main drug-metabolizing enzymes. For this purpose, rat and human hepatic subcellular fractions were incubated with CAR, CAO or HUM together with specific substrates for oxidation, reduction and conjugation enzymes and their coenzymes. HPLC, spectrophotometric and spectrofluorimetric analyses of product formations were used. All tested sesquiterpenes significantly inhibited cytochromes P4503A (CYP3A) activities in rats as well as in human hepatic microsomes, with CAO being the strongest inhibitor. A non-competitive type of inhibition was found. On the other hand, none of the tested sesquiterpenes significantly affected the activities of carbonyl-reducing enzymes (CBR1, AKRs, NQO1) or conjugation enzymes (UGTs, GSTs, SULTs, COMT). As CYP3A enzymes metabolize many drugs, their inhibition by CAO, CAR and HUM might affect the pharmacokinetics of concurrently administered drugs. Similar results obtained in rat and human hepatic microsomes indicate that rats could be used for further testing of possible drug-sesquiterpenes interactions in vivo.
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α-Humulene has shown anti-inflammatory and antitumor activity in lung, colon, prostate, and breast cancer.
“This compound has shown anti-inflammatory and antitumor activity in lung, colon, prostate, and breast cancer.”
From Clove essential oil (Syzygium aromaticum L. Myrtaceae): Extraction, chemical composition, food applications, and essential bioactivity for human health (2021) · cites this paper as [46]
α-Humulene inhibits the activity of the CYP3A enzyme, a drug-metabolizing enzyme in humans' and rats' liver microsomes.
“Nguyen et al. [46] reported that α-humulene inhibits the activity of the CYP3A enzyme, a drug-metabolizing enzyme in humans’ and rats’ liver microsomes [46].”
From Clove essential oil (Syzygium aromaticum L. Myrtaceae): Extraction, chemical composition, food applications, and essential bioactivity for human health (2021) · cites this paper as [46]
α-Humulene demonstrated antiproliferative activity and alteration of the mitochondrial cell membrane in colon cancer cells.
“Some studies reported that α-humulene demonstrated antiproliferative activity and alteration of the mitochondrial cell membrane in colon cancer cells [14,37,42,43,44,45,46].”
From Clove essential oil (Syzygium aromaticum L. Myrtaceae): Extraction, chemical composition, food applications, and essential bioactivity for human health (2021) · cites this paper as [46]
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Haro-González, J. N., Castillo-Herrera, G. A., Martínez-Velázquez, M., & Espinosa-Andrews, H. (2021) · Molecules · doi:10.3390/molecules26216387 · Cited by 463 · see citing works
- Authors
- Nguyen, L. T., Myslivečková, Z., Szotáková, B., Špičáková, A., Lněničková, K., Ambrož, M., Kubíček, V., Krasulová, K., Anzenbacher, P., & Skálová, L.
- Affiliations
- Charles University (CZ)
- Institute of Molecular and Translational Medicine (CZ)
- Corresponding author
- Skálová, Lenka
- ORCID
- Venue
- Chemico-Biological Interactions
- Publisher
- Elsevier BV
- Published
- 2017-12
- Volume
- 278
- Pages
- 123-128
- ISSN
- 0009-2797 (ISSN-L)
- OpenAlex
- W2765931675
- Cited by
- 67
- References
- 28
- Citations by year
- 2026: 6 · 2025: 15 · 2024: 5 · 2023: 4 · 2022: 7 · 2021: 9 · 2020: 9 · 2019: 9 · 2018: 3
- FWCI
- 6.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Chemico-Biological Interactions (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Czech Science Foundation (P303/12/G163)
- Charles University (SVV260294)
- Palacky University (LF_2017_012)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Sesquiterpenes and Asteraceae Studies
- Keywords
- β-caryophyllene, caryophyllene oxide, α-humulene, sesquiterpenes, drug-metabolizing enzymes, CYP3A inhibition, cytochrome P450, non-competitive inhibition, liver microsomes, phase II enzymes, essential oils, pharmacokinetics
- MeSH terms
- Monocyclic Sesquiterpenes, Polycyclic Sesquiterpenes, Animals, Anti-Inflammatory Agents, Non-Steroidal, Humans, Kinetics, Liver, Male, Microsomes, Liver, Sesquiterpenes, Rats, Wistar, Cytochrome P-450 CYP1A2, Inhibitory Concentration 50, Rats, Cytochrome P-450 CYP3A
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