beta-caryophyllene oxide and trans-nerolidol affect enzyme activity of CYP3A4 - in vitro and in silico studies
Language English Country Czech Republic Media print
Document type Journal Article
PubMed
31755290
DOI
10.33549/physiolres.934323
PII: 934323
Knihovny.cz E-resources
- MeSH
- Cytochrome P-450 CYP3A chemistry drug effects metabolism MeSH
- Farnesol chemistry pharmacology MeSH
- Cytochrome P-450 CYP3A Inhibitors pharmacology MeSH
- Microsomes, Liver enzymology MeSH
- Catalytic Domain MeSH
- Humans MeSH
- Models, Molecular MeSH
- Molecular Structure MeSH
- Polycyclic Sesquiterpenes chemistry pharmacology MeSH
- Sesquiterpenes chemistry pharmacology MeSH
- Molecular Docking Simulation MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- caryophyllene oxide MeSH Browser
- CYP3A4 protein, human MeSH Browser
- Cytochrome P-450 CYP3A MeSH
- Farnesol MeSH
- Cytochrome P-450 CYP3A Inhibitors MeSH
- nerolidol MeSH Browser
- Polycyclic Sesquiterpenes MeSH
- Sesquiterpenes MeSH
Evaluation of possible interactions with enzymes of drug metabolism is an important part of studies on safety and, in general, on the properties of any drug or biologically active compound. Here, focus is given on interactions of three sesquiterpenes (beta-caryophyllene oxide (CAO), trans-nerolidol (tNER) and farnesol (FAR)) with CYP3A4. To determine the CYP3A4 activity, specific substrates testosterone (TES) and midazolam (MDZ) were used. In human liver microsomes, the CAO inhibited the MDZ 1´-hydroxylation by mixed type inhibition and K(i) 46.6 microM; TES 6beta-hydroxylation was inhibited more strongly by tNER by the same mechanism and with K(i) of 32.5 microM. Results indicated a possibility of different mode of interaction of both compounds within the active site of CYP3A4 and this was why the molecular docking study was done. The docking experiments showed that the studied sesquiterpenes (CAO and tNER) bound to the CYP3A4 active site cause a significant decrease of binding affinity of substrates tested which corresponded well to the inhibition studies. The inhibition observed, however, most probably does not pose a real harm to microsomal drug metabolism as the levels of sesquiterpenes in plasma (assuming the use of these compounds as spices or flavoring additives) does not usually exceed micromolar range. Hence, the interaction of drugs metabolized by CYP3A4 with sesquiterpenes is less probable.
References provided by Crossref.org
In Vitro Interaction of Binuclear Copper Complexes with Liver Drug-Metabolizing Cytochromes P450