RT Journal Article
SR Electronic
T1 Oleuropein-induced acceleration of CYP-catalyzed drug metabolism: central role for nuclear receptor PPARα
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP DMD-AR-2020-000302
DO 10.1124/dmd.120.000302
A1 Foteini Malliou
A1 Christina E. Andriopoulou
A1 Frank J. Gonzalez
A1 Aristeidis Kofinas
A1 Alexios-Leandros Skaltsounis
A1 Maria Konstandi
YR 2021
UL http://dmd.aspetjournals.org/content/early/2021/06/23/dmd.120.000302.abstract
AB Oleuropein (OLE), the main constituent of olea oleuropea, displays pleiotropic beneficial effects in health and disease, which are mainly attributed to its antiinflammatory and cardioprotective properties. Several food supplements and herbal medicines contain OLE and are available without a prescription. This study investigated the effects of OLE on the main CYPs catalyzing the metabolism of many prescribed drugs. Emphasis was given on the role of peroxisome proliferator-activated receptor alpha (PPARα), a nuclear transcription factor regulating numerous genes including CYPs. 129/Sv wild-type and Ppara-null mice were treated with OLE for six weeks. OLE induced Cyp1a1, Cyp1a2, Cyp1b1, Cyp3a14, Cyp3a25, Cyp2c29, Cyp2c44, Cyp2d22 and Cyp2e1 mRNAs in liver of wild-type mice, whereas no similar effects were observed in Ppara-null mice, indicating that the OLE-induced effect on these CYPs is mediated by PPARα. Activation of the PI3k/AKT/FOX01, JNK, AKT/p70 and ERK related pathways participates in CYP induction by OLE. These data indicate that consumption of herbal medicines and food supplements containing OLE could accelerate the metabolism of drug stubstrates of the above mentioned CYPs, thus reducing their efficacy and the outcome of pharmacotherapy. Therefore, OLE-induced activation of PPARα could modify the effects of drugs due to their increased metabolism and clearance, which should be taken into account when consuming OLE-containing products with certain drugs, in particular those of narrow therapeutic window. Significance Statement This study indicated that oleuropein, which belongs to the main constituents of the leaves and olive drupes of Olea europaea, induces the synthesis of the major CYPs metabolizing the majority of prescribed drugs via activation of PPARα. This effect could modify the pharmacokinetic profile of co-administered drugs-substrates of the CYPs, thus altering their therapeutic efficacy and toxicity.