title: Induction of expression and functional activity of P-glycoprotein efflux transporter by bioactive plant natural products.
abstract: The effect of bioactive plant natural products on the expression and functional activity of P-glycoprotein (P-gp) is poorly understood. Interactions of bioactive plant-based food and dietary supplements with P-gp can cause significant alteration of pharmacokinetic properties of P-gp substrate drugs when used in combination. This can augment toxicity and/or interfere with the drug's therapeutic outcomes. This study investigated the effects of diverse commonly used plant natural products on the expression and activity of P-gp in human adenocarcinoma cells (LS-180). These natural products included the tobacco cembranoid (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol (cembratriene), the palm oil-derived γ-tocotrienol, the extra-virgin olive oil-derived secoiridoid oleocanthal, and the triterpene acid asiatic acid derived from Melaleuca ericifolia and abundant in several other common plant dietary supplements. Treatment with 25μM of cembratriene, oleocanthal, γ-tocotrienol, or asiatic acid showed 2.3-3.0-fold increase in P-gp expression as demonstrated by Western blotting. These results were consistent with those obtained by quantitative analysis of fluorescent micrographs for P-gp. Accumulation studies demonstrated 31-38% decrease in rhodamine 123 intracellular levels when LS-180 cells were treated with the investigated compounds as a result of P-gp induction. Bioactive natural products can up-regulate the P-gp expression and functionality, which may induce herb/food-drug interactions when concomitantly used with P-gp substrate drugs.
authors.affiliation: Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, United States.
authors.forename: Alaa H
authors.initials: AH
authors.lastname: Abuznait
authors.forename: Hisham
authors.initials: H
authors.lastname: Qosa
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: O'Connell
authors.forename: Jessica
authors.initials: J
authors.lastname: Akbarian-Tefaghi
authors.forename: Paul W
authors.initials: PW
authors.lastname: Sylvester
authors.forename: Khalid A
authors.initials: KA
authors.lastname: El Sayed
authors.forename: Amal
authors.initials: A
authors.lastname: Kaddoumi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000447:Aldehydes / Q000737:chemistry / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002839:Chromans / Q000737:chemistry / Q000494:pharmacology*; D000081004:Cyclopentane Monoterpenes; D019587:Dietary Supplements; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D031650:Melaleuca; D015394:Molecular Structure; D053978:Pentacyclic Triterpenes / Q000737:chemistry / Q000494:pharmacology*; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C569865:(1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000447:Aldehydes; D001688:Biological Products; D002839:Chromans; D000081004:Cyclopentane Monoterpenes; D004224:Diterpenes; D053978:Pentacyclic Triterpenes; D010636:Phenols; D014810:Vitamin E; C013649:plastochromanol 8; C017032:asiatic acid; C503534:oleocanthal