beta-caryophyllene oxide and trans-nerolidol affect enzyme activity of CYP3A4 - in vitro and in silico studies
Jazyk angličtina Země Česko Médium print
Typ dokumentu časopisecké články
PubMed
31755290
DOI
10.33549/physiolres.934323
PII: 934323
Knihovny.cz E-zdroje
- MeSH
- cytochrom P-450 CYP3A chemie účinky léků metabolismus MeSH
- farnesol chemie farmakologie MeSH
- inhibitory cytochromu P450 CYP3A farmakologie MeSH
- jaterní mikrozomy enzymologie MeSH
- katalytická doména MeSH
- lidé MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- polycyklické seskviterpeny chemie farmakologie MeSH
- seskviterpeny chemie farmakologie MeSH
- simulace molekulového dockingu MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- caryophyllene oxide MeSH Prohlížeč
- CYP3A4 protein, human MeSH Prohlížeč
- cytochrom P-450 CYP3A MeSH
- farnesol MeSH
- inhibitory cytochromu P450 CYP3A MeSH
- nerolidol MeSH Prohlížeč
- polycyklické seskviterpeny MeSH
- seskviterpeny 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.
Citace poskytuje Crossref.org
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