Istituto Comprensivo Primo, 98057 Milazzo, Italy.
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy.
Int J Mol Sci. 2024 Jun 11;25(12):6424. doi: 10.3390/ijms25126424.
Chloroquine (CQ) is a 4-aminoquinoline derivative largely employed in the management of malaria. CQ treatment exploits the drug's ability to cross the erythrocyte membrane, inhibiting heme polymerase in malarial trophozoites. Accumulation of CQ prevents the conversion of heme to hemozoin, causing its toxic buildup, thus blocking the survival of Plasmodium parasites. Recently, it has been reported that CQ is able to exert antiviral properties, mainly against HIV and SARS-CoV-2. This renewed interest in CQ treatment has led to the development of new studies which aim to explore its side effects and long-term outcome. Our study focuses on the effects of CQ in non-parasitized red blood cells (RBCs), investigating hemoglobin (Hb) functionality, the anion exchanger 1 (AE1) or band 3 protein, caspase 3 and protein tyrosine phosphatase 1B (PTP-1B) activity, intra and extracellular ATP levels, and the oxidative state of RBCs. Interestingly, CQ influences the functionality of both Hb and AE1, the main RBC proteins, affecting the properties of Hb oxygen affinity by shifting the conformational structure of the molecule towards the R state. The influence of CQ on AE1 flux leads to a rate variation of anion exchange, which begins at a concentration of 2.5 μM and reaches its maximum effect at 20 µM. Moreover, a significant decrease in intra and extracellular ATP levels was observed in RBCs pre-treated with 10 µM CQ vs. erythrocytes under normal conditions. This effect is related to the PTP-1B activity which is reduced in RBCs incubated with CQ. Despite these metabolic alterations to RBCs caused by exposure to CQ, no signs of variations in oxidative state or caspase 3 activation were recorded. Our results highlight the antithetical effects of CQ on the functionality and metabolism of RBCs, and encourage the development of new research to better understand the multiple potentiality of the drug.
氯喹（CQ）是一种 4-氨基喹啉衍生物，主要用于治疗疟疾。CQ 治疗利用药物穿过红细胞膜的能力，抑制疟原虫滋养体中的血红素聚合酶。CQ 的积累阻止了血红素转化为疟原血红素，导致其毒性积累，从而阻断疟原虫的存活。最近，据报道 CQ 能够发挥抗病毒特性，主要针对 HIV 和 SARS-CoV-2。对 CQ 治疗的重新关注导致了新的研究的开展，旨在探索其副作用和长期结果。我们的研究侧重于非寄生红细胞（RBC）中 CQ 的作用，研究血红蛋白（Hb）功能、阴离子交换器 1（AE1）或带 3 蛋白、半胱天冬酶 3 和蛋白酪氨酸磷酸酶 1B（PTP-1B）活性、细胞内和细胞外 ATP 水平以及 RBC 的氧化状态。有趣的是，CQ 影响 Hb 和 AE1 这两种 RBC 主要蛋白的功能，通过将分子构象结构向 R 状态转变来影响 Hb 氧亲和力的性质。CQ 对 AE1 通量的影响导致阴离子交换速率发生变化，这种变化始于 2.5 μM 的浓度，并在 20 μM 时达到最大效应。此外，与正常条件下的红细胞相比，用 10 μM CQ 预处理的 RBC 中观察到细胞内和细胞外 ATP 水平显著降低。这种作用与 PTP-1B 活性有关，PTP-1B 活性在与 CQ 孵育的 RBC 中降低。尽管 CQ 暴露会导致 RBC 发生这些代谢改变，但未记录到氧化状态或半胱天冬酶 3 激活的变化迹象。我们的结果强调了 CQ 对 RBC 功能和代谢的对立作用，并鼓励开展新的研究以更好地了解药物的多种潜在性。
