β-caryophyllene oxide and trans -nerolidol affect enzyme activity of CYP3A4 – in vitro and in silico studies.

摘要

Evaluation of possible interactions with enzymes of drugmetabolism is an important part of studies on safety and,in general, on the properties of any drug or biologically activecompound. Here, focus is given on interactions of threesesquiterpenes (β-caryophyllene oxide (CAO), trans -nerolidol(tNER) and farnesol (FAR)) with CYP3A4. To determine theCYP3A4 activity, specific substrates testosterone (TES) andmidazolam (MDZ) were used. In human liver microsomes, theCAO inhibited the MDZ 1′-hydroxylation by mixed type inhibitionand Ki 46.6 μM; TES 6β-hydroxylation was inhibited morestrongly by tNER by the same mechanism and with Ki of 32.5 μM.Results indicated a possibility of different mode of interaction ofboth compounds within the active site of CYP3A4 and this waswhy the molecular docking study was done. The dockingexperiments showed that the studied sesquiterpenes (CAO andtNER) bound to the CYP3A4 active site cause a significantdecrease of binding affinity of substrates tested whichcorresponded well to the inhibition studies. The inhibitionobserved, however, most probably does not pose a real harm tomicrosomal drug metabolism as the levels of sesquiterpenes inplasma (assuming the use of these compounds as spices orflavoring additives) does not usually exceed micromolar range.Hence, the interaction of drugs metabolized by CYP3A4 withsesquiterpenes is less probable.