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Inhibition of organic cation transporter (OCT) activities by carcinogenic heterocyclic aromatic amines

Katia Sayyed¹, Christophe Camillerapp², Marc Le Vée²

¹Institut de recherche en santé, environnement et travail, UMR_S 1085, 2 Avenue du Pr Léon Bernard, Rennes 35043, France; Faculty of Sciences, EDST-AZM-Center-LBA3B, Lebanese University, Rafic Hariri Campus, Lebanon.

Toxicology in Vitro : an International Journal Published in Association with BIBRA

|September 7, 2018

Abstract:

Carcinogenic heterocyclic aromatic amines (HAAs) interact with some drug transporters, like the efflux pump BCRP and the organic anion transporters OAT1 and OAT3. The present study was designed to determine whether they can also target activities of the organic cation transporters (OCTs), using mainly OCT1-, OCT2- and OCT3-overexpressing HEK293 cells. Fifteen HAAs were demonstrated to differently alter OCT activities; with a cut-off of at least 50% reduction of transporter activity by 100 μM HAAs, 5/15 HAAs, including Trp-P-1 and Trp-P-2, inhibited activities of OCT1, OCT2 and OCT3, whereas 7/15 HAAs, including PhIP and MeIQx, blocked those of OCT2 and OCT3, 1/15 HAAs reduced those of OCT1 and OCT2 and 2/15 HAAs, including AαC, only that of OCT2. IC₅₀ values of Trp-P-1 and Trp-P-2 towards OCT activities were found to be in the 2-6 μM range, likely not relevant for human exposure to HAAs through smoking or the diet. Trp-P-1 and Trp-P-2 additionally failed to trans-stimulate OCT1 and OCT2 activities and exhibited similar accumulation in OCT1/2-transduced HEK293 cells and control HEK293-MOCK cells. These data demonstrate that HAAs, notably Trp-P-1 and Trp-P-2, interact with OCT1/2, without however being transported, thus likely discarding a major role for OCT1/2 in HAA systemic toxicokinetics.

Insights

Carcinogenic heterocyclic aromatic amines (HAAs) can inhibit organic cation transporters (OCTs). While some HAAs interact with OCT1, OCT2, and OCT3, they are not transported, suggesting OCTs play a minor role in HAA toxicokinetics.

Area of Science:

Pharmacology
Toxicology
Molecular Biology

Background:

Carcinogenic heterocyclic aromatic amines (HAAs) are known to interact with drug transporters.
Previous studies identified interactions with BCRP, OAT1, and OAT3.
The interaction of HAAs with organic cation transporters (OCTs) remains largely unexplored.

Purpose of the Study:

To investigate the interaction of various HAAs with organic cation transporters (OCTs).
To determine if HAAs affect the activity of OCT1, OCT2, and OCT3.
To assess the potential role of OCTs in the systemic toxicokinetics of HAAs.

Main Methods:

Utilized HEK293 cells overexpressing OCT1, OCT2, and OCT3.
Assessed the inhibitory effects of 15 different HAAs on OCT activities.
Determined IC50 values for specific HAAs and evaluated their transport by OCTs.

Main Results:

Fifteen HAAs exhibited varying degrees of inhibition on OCT activities.
Trp-P-1 and Trp-P-2 significantly inhibited OCT1, OCT2, and OCT3 at low micromolar concentrations.
PhIP and MeIQx blocked OCT2 and OCT3 activities.
Trp-P-1 and Trp-P-2 were not transported by OCT1/2, indicating a non-transport interaction.

Conclusions:

Heterocyclic aromatic amines (HAAs) interact with organic cation transporters (OCTs), particularly OCT1, OCT2, and OCT3.
The interaction involves inhibition of transporter activity but not substrate transport.
OCT1 and OCT2 are unlikely to play a significant role in the systemic toxicokinetics of HAAs.

Read full analysis

Keywords:

Drug transporter Heterocyclic amines Organic cation transporter Toxicity Toxicokinetics

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