Institut 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.
Institut de recherche en santé, environnement et travail, UMR_S 1085, 2 Avenue du Pr Léon Bernard, Rennes 35043, France.
Toxicol In Vitro. 2019 Feb;54:10-22. doi: 10.1016/j.tiv.2018.08.015. Epub 2018 Sep 3.
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. IC 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.
致癌杂环芳香胺 (HAAs) 与一些药物转运蛋白相互作用，如外排泵 BCRP 和有机阴离子转运蛋白 OAT1 和 OAT3。本研究旨在确定它们是否也能靶向有机阳离子转运体 (OCTs) 的活性，主要使用 OCT1-、OCT2- 和 OCT3 过表达的 HEK293 细胞。15 种 HAAs 被证明可不同程度地改变 OCT 活性；以 100µM HAAs 至少降低 50%转运体活性为截断值，5/15 种 HAAs，包括 Trp-P-1 和 Trp-P-2，抑制了 OCT1、OCT2 和 OCT3 的活性，而 7/15 种 HAAs，包括 PhIP 和 MeIQx，阻断了 OCT2 和 OCT3 的活性，1/15 种 HAAs 降低了 OCT1 和 OCT2 的活性，2/15 种 HAAs，包括 AαC，仅降低了 OCT2 的活性。发现 Trp-P-1 和 Trp-P-2 对 OCT 活性的 IC 值在 2-6µM 范围内，对于通过吸烟或饮食暴露于 HAAs 的人类来说可能并不相关。Trp-P-1 和 Trp-P-2 此外未能跨刺激 OCT1 和 OCT2 活性，并在 OCT1/2 转导的 HEK293 细胞和对照 HEK293-MOCK 细胞中表现出相似的积累。这些数据表明，HAAs，特别是 Trp-P-1 和 Trp-P-2，与 OCT1/2 相互作用，但不被转运，因此可能排除了 OCT1/2 在 HAA 全身毒代动力学中的主要作用。
