title: Modulation of CYPs, P-gp, and PXR by Eschscholzia californica (California Poppy) and Its Alkaloids.
abstract: Eschscholzia californica, a native US plant, is traditionally used as a sedative, analgesic, and anxiolytic herb. With the rapid rise in the use of herbal supplements together with over-the-counter and prescription drugs, the risk for potential herb-drug interactions is also increasing. Most of the clinically relevant pharmacokinetic drug interactions occur due to modulation of cytochrome P450 enzymes (CYPs), P-glycoprotein, and the pregnane X receptor by concomitantly used herbs. This study aimed to determine the effects of an EtOH extract, aqueous extract (tea), basic CHCl3 fractions, and isolated major alkaloids, namely protopine (1), escholtzine (2), allocryptopine (3), and californidine (4), of E. californica on the activity of cytochrome P450s, P-glycoprotein and the pregnane X receptor. The EtOH extract and fractions showed strong time-dependent inhibition of CYP 3A4, CYP 2C9, and CYP 2C19, and reversible inhibition of CYP 2D6. Among the alkaloids, escholtzine (2) and allocryptopine (3) exhibited time-dependent inhibition of CYP 3A4, CYP 2C9, and CYP 2C19 (IC50 shift ratio > 2), while protopine (1) and allocryptopine (3) showed reversible inhibition of CYP 2D6 enzyme. A significant activation of the pregnane X receptor (> 2-fold) was observed with the EtOH extract, basic CHCl3 fraction, and alkaloids (except protopine), which resulted into an increased expression of mRNA and the activity of CYP 3A4 and CYP 1A2. The expression of P-glycoprotein was unaffected. However, aqueous extract (tea) and its main alkaloid californidine (4) did not affect cytochrome P450s, P-glycoprotein, or the pregnane X receptor. This data suggests that EtOH extract of E. californica and its major alkaloids have a potential of causing interactions with drugs that are metabolized by cytochrome P450s, while the tea seems to be safer.
authors.affiliation: National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS, USA.
authors.forename: Vamshi K
authors.initials: VK
authors.lastname: Manda
authors.affiliation: National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS, USA.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Ibrahim
authors.affiliation: National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS, USA.
authors.forename: Olivia R
authors.initials: OR
authors.lastname: Dale
authors.affiliation: National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS, USA.
authors.forename: Mallika
authors.initials: M
authors.lastname: Kumarihamy
authors.affiliation: Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Cutler
authors.affiliation: National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS, USA.
authors.forename: Ikhlas A
authors.initials: IA
authors.lastname: Khan
authors.affiliation: National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS, USA.
authors.forename: Larry A
authors.initials: LA
authors.lastname: Walker
authors.affiliation: National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS, USA.
authors.forename: Ilias
authors.initials: I
authors.lastname: Muhammad
authors.affiliation: National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS, USA.
authors.forename: Shabana I
authors.initials: SI
authors.lastname: Khan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D053119:Benzophenanthridines / Q000494:pharmacology; D001600:Berberine Alkaloids / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004149:Dioxoles / Q000494:pharmacology; D004285:Dogs; D031675:Eschscholzia / Q000737:chemistry*; D056945:Hep G2 Cells / Q000187:drug effects; D041743:Herb-Drug Interactions; D006801:Humans; D061985:Madin Darby Canine Kidney Cells / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000470:Alkaloids; D053119:Benzophenanthridines; D001600:Berberine Alkaloids; D004149:Dioxoles; D010936:Plant Extracts; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; C510123:californidine; C510124:escholtzine; D003577:Cytochrome P-450 Enzyme System; C109505:allocryptopine; C009093:protopine