title: The in vitro inhibitory potential of trade herbal products on human CYP2D6-mediated metabolism and the influence of ethanol.
abstract: The six commonly used trade herbal products, St. John's wort, common valerian, common sage, Ginkgo biloba, Echinacea purpurea and horse chestnut, and ethanol, were investigated for their in vitro inhibitory potential of cytochrome P450 2D6 (CYP2D6)-mediated metabolism. Herbal components were extracted from commercially available products in a way that ensured the same composition of constituents in the extract as in the original trade products. c-DNA baculovirus expressed CYP2D6 was used with dextromethorphan as substrate. Quinidine was included as a positive control inhibitor. A validated high performance liquid chromatography methodology was used to quantify the formation of dextrorphan (product of dextromethorphan O-demethylation). Ethanol showed a biphasic effect on CYP2D6 metabolism, increasing initially the CYP2D6 activity with 175% of control up to a concentration of 1.1%, where after ethanol linearly inhibited the CYP2D6 activity. All the investigated herbs inhibited CYP2D6 activity to some extent, but only St. John's wort, common sage and common valerian were considered possible candidates for in vivo clinically significant effects. They showed IC50 values of 0.07 +/- 7 x 10(-3) mg/ml, 0.8 +/- 0.05 mg/ml and 1.6 +/- 0.2 mg/ml, respectively. St. John's wort inhibited CYP2D6-mediated metabolism in an uncompetitive manner, while common valerian and common sage in a non-competitive manner demonstrated interherb differences in inhibition patterns and differences when compared to the more homogenous competitive inhibitor quinidine. Common valerian was the only herb that showed a mechanistic inhibition of CYP2D6 activity and attention should be paid to a possible toxicity of this herb.
authors.affiliation: Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway. bent.h.hellum@ntnu.no
authors.forename: Bent H
authors.initials: BH
authors.lastname: Hellum
authors.forename: Odd Georg
authors.initials: OG
authors.lastname: Nilsen
mesh_terms: D001711:Biotransformation; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000032:analysis; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003915:Dextromethorphan / Q000378:metabolism; D004791:Enzyme Inhibitors; D000431:Ethanol / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D010936:Plant Extracts / Q000494:pharmacology; D028321:Plant Preparations / Q000494:pharmacology*; D011802:Quinidine / Q000494:pharmacology
chemical_list: D002492:Central Nervous System Depressants; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D010936:Plant Extracts; D028321:Plant Preparations; D000431:Ethanol; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6; D011802:Quinidine