Human and Environmental Toxicology, University of Konstanz, 78457, Konstanz, Germany; School of Pharmaceutical Sciences, Shoolini University, Solan, 173212, India.
Department of Chemistry, University of Konstanz, 78457, Konstanz, Germany.
Chem Biol Interact. 2019 Sep 25;311:108761. doi: 10.1016/j.cbi.2019.108761. Epub 2019 Jul 23.
Water contamination by cyanobacterial blooms is a worldwide health hazard to humans as well as livestock. Exposure to Microcystins (MCs), toxins produced by various cyanobacterial or blue green algae found in poorly treated drinking water or contaminated seafood such as fish or prawns are associated with hepatotoxicity, nephropathy and neurotoxicity and in extreme cases, death in humans. MC congeners, currently >240 known, differ dramatically in their uptake kinetics, i.e. their uptake via OATP1B1 and OATP1B3, in OATP overexpressing human HEK293 cells and primary human hepatocytes. It is thus likely that MC congeners will also differ with respect to the cellular efflux of the parent and conjugated congeners, e.g. via MRPs, MDRs, BCRP or BSEP. Consequently, the role and kinetics of different human efflux transporters - MRP, MDR, BCRP and BSEP in MC efflux was studied using insect membrane vesicles overexpressing the human transporters of interest. Of the efflux transporters investigated, MRP2 displayed MC transport. Michaelis-Menten kinetics displayed mild co-operativity and thus allosteric behavior of MRP2. MC transport by MRP2 was MC congener-specific, whereby MC-LF was transported more rapidly than MC-LR and -RR. Other human transporters (BCRP, BSEP, MRP1,3,5, MDR1) tested in this study did not exhibit interaction with MC. Although MRP2 showed specific MC transport, the MC-LR-GSH conjugate, was not transported suggesting the involvement of other transporters than MRP2 for the conjugate efflux.
水藻水华污染是全世界范围内人类和牲畜的健康危害。接触到微囊藻毒素（MCs），这种毒素由各种蓝藻或蓝绿藻产生，存在于处理不当的饮用水或受污染的海鲜中，如鱼类或虾类，与肝毒性、肾毒性和神经毒性有关，在极端情况下，还会导致人类死亡。目前已知的 MC 同系物有>240 种，它们在人源 HEK293 细胞和原代人肝细胞中通过 OATP1B1 和 OATP1B3 的摄取动力学，即摄取动力学，存在显著差异。因此，MC 同系物在母体和共轭同系物的细胞外排方面也可能存在差异，例如通过 MRP、MDR、BCRP 或 BSEP。因此，使用过表达人源转运蛋白的昆虫膜囊泡研究了不同的人外排转运蛋白（MRP、MDR、BCRP 和 BSEP）在 MC 外排中的作用和动力学。在所研究的外排转运蛋白中，MRP2 显示出 MC 转运。米氏动力学显示出轻度协同作用，因此 MRP2 具有变构行为。MRP2 对 MC 的转运具有 MC 同系物特异性，其中 MC-LF 的转运速度快于 MC-LR 和 -RR。在这项研究中测试的其他人类转运蛋白（BCRP、BSEP、MRP1、3、5、MDR1）没有显示与 MC 的相互作用。尽管 MRP2 显示出特定的 MC 转运，但 MC-LR-GSH 轭合物没有被转运，这表明轭合物外排涉及除 MRP2 以外的其他转运蛋白。
