Cadmium transport by mammalian ATP-binding cassette transporters

Abstract

Cellular responses to toxic metals depend on metal accessibility to intracellular targets, reaching interaction sites, and the intracellular metal concentration, which is mainly determined by uptake pathways, binding/sequestration and efflux pathways. ATP-binding cassette (ABC) transporters are ubiquitous in the human body—usually in epithelia—and are responsible for the transfer of indispensable physiological substrates (e.g. lipids and heme), protection against potentially toxic substances, maintenance of fluid composition, and excretion of metabolic waste products. Derailed regulation and gene variants of ABC transporters culminate in a wide array of pathophysiological disease states, such as oncogenic multidrug resistance or cystic fibrosis. Cadmium (Cd) has no known physiological role in mammalians and poses a health risk due to its release into the environment as a result of industrial activities, and eventually passes into the food chain. Epithelial cells, especially within the liver, lungs, gastrointestinal tract and kidneys, are particularly susceptible to the multifaceted effects of Cd because of the plethora of uptake pathways available. Pertinent to their broad substrate spectra, ABC transporters represent a major cellular efflux pathway for Cd and Cd complexes. In this review, we summarize current knowledge concerning transport of Cd and its complexes (mainly Cd bound to glutathione) by the ABC transporters ABCB1 (P-glycoprotein, MDR1), ABCB6, ABCC1 (multidrug resistance related protein 1, MRP1), ABCC7 (cystic fibrosis transmembrane regulator, CFTR), and ABCG2 (breast cancer related protein, BCRP). Potential detoxification strategies underlying ABC transporter-mediated efflux of Cd and Cd complexes are discussed.

Global threat posed by metals and metalloids in the changing environment: a One Health approach to mechanisms of toxicity

“…The tripeptide antioxidant glutathione (GSH) avidly binds Cd and is also a common substrate for multiple effluxing ABC transporters. As critically reviewed by Thévenod and Lee (2024), these Cd-GSH complexes could be potentially transported by selected ABC transporters (ABCB6, ABCC1, ABCC7, ABCG2) expressed in the airways, liver, kidney and gastrointestinal tract, and influence the cellular, tissue and bodily distribution of Cd and Cd-GSH complexes in addition to their detoxification.…”

“…The impact of metals on microbial health provides insight into their mutual and symbiotic relationship (Ghio and Hilborn 2023;Ke et al 2023;Turner 2023) whereas metal detoxification and adaptive strategies in eukaryotes (Dallinger 2024;Putra et al 2023; Thévenod and Lee 2024) demonstrate important consequences of environmental and, in particular, soil health on plant and animal health. In mammalians, speciation of MMs determines their transport modality in the blood (Doroudian et al 2023) and distribution within cells, tissues and organs (Thévenod and Lee 2024). At the cellular level, metals directly interact with numerous biological molecules, such as lipids (Issler et al 2024), eliciting toxicity and cell death (Pradhan et al 2024;Shao et al 2024).…”

Toward a Mechanism-Driven Integrated Framework to Link Human Exposure to Multiple Toxic Metal(loid) Species with Environmental Diseases

“…The fact that multiple metal-containing metabolites were observed in these experiments—two for CH 3 Hg + and Hg 2+ and four for Cd 2+ —suggests that the actual translocation mechanisms, which must involve the uptake of the mobilized metal species into different toxicological target organs may be more elaborate than the mere formation and translocation of just a single metal–SMW thiol complex to an organ. Thus, the known ATP-binding biomolecular ABC-cassette transporters, which are differently expressed on the surface of target organ cells, such as the liver, the kidneys and the lung [ 94 ], will determine which of the Cys/hCys containing CH 3 Hg + , Hg 2+ and Cd 2+ metabolites that are formed in the bloodstream are actually translocated to the toxicological target organs [different transporters will recognize structurally different toxic metal(loid)–Cys/hCys complexes].…”

Modulation of the Adverse Health Effects of Environmental Cadmium Exposure by Zinc and Its Transporters

“…Cd can reach most cells in the body in the same way as metal nutrients, Zn, Fe, Ca, and Cu. Indeed, the cellular acquisition of Cd appeared to be through many more transporters than those mediate Cd entry into the enterocytes [88,89]. Of note, however, no excretory mechanism has been found for Cd.…”