Affordable Access

deepdyve-link
Publisher Website

Potent inhibition of human organic cation transporter 2 (hOCT2) by β-carboline alkaloids.

Authors
  • Wagner, David J1
  • Duan, Haichuan1
  • Chapron, Alenka1
  • Lee, Richard W2
  • Wang, Joanne1
  • 1 a Department of Pharmaceutics , University of Washington , Seattle , WA , USA and.
  • 2 b School of Pharmacy, University of Washington , Seattle , WA , USA.
Type
Published Article
Journal
Xenobiotica; the fate of foreign compounds in biological systems
Publication Date
Dec 01, 2017
Volume
47
Issue
12
Pages
1112–1120
Identifiers
DOI: 10.1080/00498254.2016.1271160
PMID: 27977936
Source
Medline
Keywords
License
Unknown

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 IC50 values 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.

Report this publication

Statistics

Seen <100 times