Department of Physiology, Pathophysiology & Toxicology and ZBAF (Centre for Biomedical Education and Research), Faculty of Health, School of Medicine, Witten/Herdecke University, Stockumer Str 12 (Thyssenhaus), 58453, Witten, Germany.
Biometals. 2019 Jun;32(3):469-489. doi: 10.1007/s10534-019-00176-6. Epub 2019 Jan 30.
Cadmium (Cd) is a toxic and non-essential divalent metal ion in eukaryotic cells. Cells can only be targeted by Cd if it hijacks physiological high-affinity entry pathways, which transport essential divalent metal ions in a process termed "ionic and molecular mimicry". Hence, "free" Cd ions and Cd complexed with small organic molecules are transported across cellular membranes via ion channels, carriers and ATP hydrolyzing pumps, whereas receptor-mediated endocytosis (RME) internalizes Cd-protein complexes. Only Cd transport pathways validated by stringent methodology, namely electrophysiology, Cd tracer studies, inductively coupled plasma mass spectrometry, atomic absorption spectroscopy, Cd-sensitive fluorescent dyes, or specific ligand binding and internalization assays for RME are reviewed whereas indirect correlative studies are excluded. At toxicologically relevant concentrations in the submicromolar range, Cd permeates voltage-dependent Ca channels ("T-type" Ca3.1, CatSper), transient receptor potential (TRP) channels (TRPA1, TRPV5/6, TRPML1), solute carriers (SLCs) (DMT1/SLC11A2, ZIP8/SLC39A8, ZIP14/SLC39A14), amino acid/cystine transporters (SLC7A9/SLC3A1, SLC7A9/SLC7A13), and Cd-protein complexes are endocytosed by the lipocalin-2/NGAL receptor SLC22A17. Cd transport via the mitochondrial Ca uniporter, ATPases ABCC1/2/5 and transferrin receptor 1 is likely but requires further evidence. Cd flux occurs through the influx carrier OCT2/SLC22A2, efflux MATE proteins SLC47A1/A2, the efflux ATPase ABCB1, and RME of Cd-metallothionein by the receptor megalin (low density lipoprotein receptor-related protein 2, LRP2):cubilin albeit at high concentrations thus questioning their relevance in Cd loading. Which Cd-protein complexes are internalized by megalin:cubilin in vivo still needs to be determined. A stringent conservative and reductionist approach is mandatory to verify relevance of transport pathways for Cd toxicity and to overcome dissemination of unsubstantiated conjectures.
镉（Cd）是真核细胞中一种有毒的、非必需的二价金属离子。只有当 Cd 劫持生理上高亲和力的进入途径时，细胞才会受到 Cd 的靶向攻击，这些途径在称为“离子和分子模拟”的过程中运输必需的二价金属离子。因此，“游离”Cd 离子和与小分子有机化合物配位的 Cd 离子通过离子通道、载体和水解 ATP 的泵穿过细胞膜，而受体介导的内吞作用（RME）则将 Cd-蛋白复合物内化。只有通过严格的方法验证的 Cd 转运途径，即电生理学、Cd 示踪研究、电感耦合等离子体质谱、原子吸收光谱法、Cd 敏感荧光染料，或用于 RME 的特异性配体结合和内化测定，才被综述，而间接相关研究则被排除在外。在亚微摩尔范围内具有毒理学相关性的浓度下，Cd 可渗透电压依赖性 Ca 通道（“T 型”Ca3.1、CatSper）、瞬时受体电位（TRP）通道（TRPA1、TRPV5/6、TRPML1）、溶质载体（SLCs）（DMT1/SLC11A2、ZIP8/SLC39A8、ZIP14/SLC39A14）、氨基酸/半胱氨酸转运体（SLC7A9/SLC3A1、SLC7A9/SLC7A13）和 Cd-蛋白复合物被脂联素-2/NGAL 受体 SLC22A17 内吞。通过线粒体 Ca 单向转运蛋白、ATP 酶 ABCC1/2/5 和转铁蛋白受体 1 进行的 Cd 转运很可能，但需要进一步的证据。Cd 流通过流入载体 OCT2/SLC22A2 发生，通过外排 MATE 蛋白 SLC47A1/A2、外排 ATP 酶 ABCB1 和受体 megalin（低密度脂蛋白受体相关蛋白 2，LRP2）：cubilin 进行 RME，形成 Cd-金属硫蛋白，但仅在高浓度下，这质疑了它们在 Cd 加载中的相关性。体内哪些 Cd-蛋白复合物被 megalin：cubilin 内化仍有待确定。为了验证 Cd 毒性的转运途径的相关性，并克服未证实的推测的传播，必须采用严格的保守和简化方法。
