title: Potent inhibition of human organic cation transporter 2 (hOCT2) by β-carboline alkaloids.
abstract: 1. Beta-carbolines are indole alkaloids with a wide range of pharmacological and toxicological activities. Beta-carbolines are structurally related to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+), a known substrate of organic cation transporters (OCTs). The goal of this study is to determine the interaction of β-carbolines with human OCT1, 2, and 3 (SLC22A1-3). 2. Dose-dependent inhibition studies were performed for five commercially available β-carbolines using a fluorescent substrate assay in HEK293 cells stably expressing hOCT1-3. The substrate potential was evaluated by uptake assays and the impact of active transport on cellular toxicity examined. 3. All tested β-carbolines potently inhibited hOCT2 with IC50values in the sub- or low micromolar range. Harmaline is the most potent hOCT2 inhibitor (IC50=0.50 ± 0.08 μM). hOCT1 and hOCT3 are less sensitive to β-carboline inhibition. Harmaline, norharmanium, and 2,9-dimethyl-4,9-dihydro-3H-β-carbolinium accumulated 2- to 7-fold higher in cells expressing hOCT1-3. HEK293 cells expressing hOCT1-3 were 6.5- to 13-fold more sensitive to harmane and norharmanium toxicity. 4. Our data support a significant role of hOCT1-3 in tissue uptake and disposition of β-carbolines. Importantly, the potent inhibition of hOCT2 by β-carbolines also raises the concern of potential drug interactions between naturally occurring bioactive alkaloids and drugs eliminated by hOCT2.
authors.affiliation: a Department of Pharmaceutics , University of Washington , Seattle , WA , USA and.
authors.forename: David J
authors.initials: DJ
authors.lastname: Wagner
authors.affiliation: a Department of Pharmaceutics , University of Washington , Seattle , WA , USA and.
authors.forename: Haichuan
authors.initials: H
authors.lastname: Duan
authors.affiliation: a Department of Pharmaceutics , University of Washington , Seattle , WA , USA and.
authors.forename: Alenka
authors.initials: A
authors.lastname: Chapron
authors.affiliation: b School of Pharmacy, University of Washington , Seattle , WA , USA.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Lee
authors.affiliation: a Department of Pharmaceutics , University of Washington , Seattle , WA , USA and.
authors.forename: Joanne
authors.initials: J
authors.lastname: Wang
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D002243:Carbolines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors*; D000075102:Organic Cation Transporter 2
chemical_list: D000470:Alkaloids; D002243:Carbolines; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human; C010262:norharman
keywords: drug interactions; hOCT2; inhibitor; organic cation transporters; β-Carbolines