Cadmium transport by human Nramp 2 expressed in Xenopus laevis oocytes

Okubo, Masato; Yamada, Kyohei; Hosoyamada, Makoto; Shibasaki, Toshiaki; Endou, Hitoshi

doi:10.1016/s0041-008x(02)00078-9

Cited by 64 publications

(40 citation statements)

References 19 publications

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“…In mammalian-cultured cells, many studies of Cd transport and inhibition of divalent cation transport by Cd have shown Cd uptake and toxicity (11,42,43,(60)(61), but there were no studies correlating Cd uptake with toxicity in any organ or specific cell type of any intact vertebrate.…”

Section: Discussionmentioning

confidence: 99%

Identification of mouse SLC39A8 as the transporter responsible for cadmium-induced toxicity in the testis

Dalton

Wang

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

267

234

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Testicular necrosis is a sensitive endpoint for cadmium (Cd 2؉ , Cd) toxicity across all species tested. Resistance to Cd-induced testicular damage is a recessive trait assigned to the Cdm locus on mouse chromosome 3. We first narrowed the Cdm-gene-containing region to 880 kb. SNP analysis of this region from two sensitive and two resistant inbred strains demonstrated a 400-kb haplotype block consistent with the Cd-induced toxicity phenotype; in this region is the Slc39a8 gene encoding a member of the solute-carrier superfamily. Slc39a8 encodes SLC39A8 (ZIP8), whose homologs in plant and yeast are putative zinc transporters. We show here that ZRT-, IRT-like protein (ZIP)8 expression in cultured mouse fetal fibroblasts leads to a >10-fold increase in the rate of intracellular Cd influx and accumulation and 30-fold increase in sensitivity to Cd-induced cell death. The complete ZIP8 mRNA and intron-exon splice junctions have no nucleotide differences between two sensitive and two resistant strains of mice; by using situ hybridization, we found that ZIP8 mRNA is prominent in the vascular endothelial cells of the testis of the sensitive strains of mice but absent in these cells of resistant strains. Slc39a8 is therefore the Cdm gene, defining sensitivity to Cd toxicity specifically in vascular endothelial cells of the testis. metal influx ͉ vascular endothelial cells ͉ solute carrier gene superfamily ͉ in situ hybridization C d is a toxic and carcinogenic nonessential metal (1), which can enter the body through the intestine, skin, and lung and accumulates in the kidney (1-3). The level of Cd in the environment has risen with advances in industrialization, and the role of Cd in human disease is of increasing concern. The mechanisms of Cd toxicity are poorly understood, although it is known that Cd exerts its effects intracellularly, and there are polypeptides such as metallothionein (4) and reduced glutathione (5) that bind Cd and afford protection. The subcellular events by which Cd is taken up by cells or removed from cells remain obscure, although such knowledge could provide potential therapeutic targets for protection or intervention against Cd toxicity. Several proteins transport Cd into bacteria, yeast, plants, and mammalian cells in culture (6-11), but their specific roles in causing toxicity are unclear; these studies underscore the difficulties in extrapolating from observations in cell culture to the intact animal.Nature has provided a fascinating genetic system as a foothold into identifying a gene involved in Cd toxicity. It is known that Cd-induced testicular necrosis is common across all animal species having testes: rodents, opossum, armadillos, frogs, pigeons, roosters, and fish (12-17). Cellular events that precede Cd-induced testicular toxicity indicate that vascular endothelial cell injury is the earliest and, perhaps, the causative event (16,(18)(19)(20)(21)(22)(23)(24).Some inbred mouse strains are resistant to Cd-induced testicular toxicity (25). The resistance phenotype segregates largely as a...

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Section: Discussionmentioning

confidence: 99%

Identification of mouse SLC39A8 as the transporter responsible for cadmium-induced toxicity in the testis

Dalton

Wang

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

267

234

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“…In oocytes microinjected with mRNA encoding DMT1, and then analyzed using two-microelectrode voltage-clamp techniques, the presence of Cd 2+ in the extracellular medium was shown to invoke a large inward current, indicating that Cd 2+ is a substrate of DMT1 (Gunshin et al, 1997). Additionally, findings of Okubo et al (2003) indicate that when oocytes are microinjected with mRNA encoding DMT1, and then subsequently exposed to CdCl 2 , the rates of inward Cd 2+ flux are much greater than those in control oocytes. Furthermore, this transport appears to be saturable, with a Michaelis-Menten constant (K m ) of approximately 1.0 μM (Okubo et al, 2003).…”

Section: Mimicry and Intestinal Transport Of CD 2+mentioning

confidence: 96%

“…Additionally, findings of Okubo et al (2003) indicate that when oocytes are microinjected with mRNA encoding DMT1, and then subsequently exposed to CdCl 2 , the rates of inward Cd 2+ flux are much greater than those in control oocytes. Furthermore, this transport appears to be saturable, with a Michaelis-Menten constant (K m ) of approximately 1.0 μM (Okubo et al, 2003).…”

Section: Mimicry and Intestinal Transport Of CD 2+mentioning

confidence: 99%

“…Considering this, we can hypothesize that when Cd 2+ is presented to a stronger nucleophilic ligand, it is released from the carrier ligand to bind to DMT1 or other transporters at the plasma membrane of the enterocyte, which allows it to be transported across the luminal plasma membrane as a cationic species. Indeed, numerous studies have provided evidence for the transport of Cd 2+ , by DMT1, as a cationic species (Elisma and Jumarie, 2001;Leazer et al, 2002;Lecoeur et al, 2002;Okubo et al, 2003;Park et al, 2002;Picard et al, 2000;Tallkvist et al, 2001). Findings from Xenopus laevis oocytes have provided some of the most direct evidence for the transport of Cd 2+ by DMT1 (Gunshin et al, 1997;Okubo et al, 2003).…”

Section: Mimicry and Intestinal Transport Of CD 2+mentioning

confidence: 99%

“…Indeed, numerous studies have provided evidence for the transport of Cd 2+ , by DMT1, as a cationic species (Elisma and Jumarie, 2001;Leazer et al, 2002;Lecoeur et al, 2002;Okubo et al, 2003;Park et al, 2002;Picard et al, 2000;Tallkvist et al, 2001). Findings from Xenopus laevis oocytes have provided some of the most direct evidence for the transport of Cd 2+ by DMT1 (Gunshin et al, 1997;Okubo et al, 2003). In oocytes microinjected with mRNA encoding DMT1, and then analyzed using two-microelectrode voltage-clamp techniques, the presence of Cd 2+ in the extracellular medium was shown to invoke a large inward current, indicating that Cd 2+ is a substrate of DMT1 (Gunshin et al, 1997).…”

Section: Mimicry and Intestinal Transport Of CD 2+mentioning

confidence: 99%

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Molecular and ionic mimicry and the transport of toxic metals

Bridges

Zalups

2005

Toxicology and Applied Pharmacology

676

460

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Despite many scientific advances, human exposure to, and intoxication by, toxic metal species continues to occur. Surprisingly, little is understood about the mechanisms by which certain metals and metal-containing species gain entry into target cells. Since there do not appear to be transporters designed specifically for the entry of most toxic metal species into mammalian cells, it has been postulated that some of these metals gain entry into target cells, through the mechanisms of ionic and/or molecular mimicry, at the site of transporters of essential elements and/or molecules. The primary purpose of this review is to discuss the transport of selective toxic metals in target organs and provide evidence supporting a role of ionic and/or molecular mimicry. In the context of this review, molecular mimicry refers to the ability of a metal ion to bond to an endogenous organic molecule to form an organic metal species that acts as a functional or structural mimic of essential molecules at the sites of transporters of those molecules. Ionic mimicry refers to the ability of a cationic form of a toxic metal to mimic an essential element or cationic species of an element at the site of a transporter of that element. Molecular and ionic mimics can also be sub-classified as structural or functional mimics. This review will present the established and putative roles of molecular and ionic mimicry in the transport of mercury, cadmium, lead, arsenic, selenium, and selected oxyanions in target organs and tissues.

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Reciprocal inhibition of Cd and Pb sulfocomplexes for uptake in Caco‐2 cells

Aduayom

Jumarie

2005

J Biochem & Molecular Tox

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Cadmium-lead interactions for uptake were studied in the TC7 clone of human enterocytic-like Caco-2 cells as a function of inorganic metal speciation. We have previously shown that Cd uptake in these cells involves both the free cation Cd2+ and chlorocomplex (CdCln(2-n)) species. Here we show 1.9 times higher uptake levels for 109CdCln(2-n) compared to 210PbCln(2-n). Reciprocal inhibitions of chlorocomplexes were observed with a much higher inhibitory effect of Cd compared to Pb. Replacing Cl- by NO3- increased both the level of aquo ion 109Cd2+ and 109Cd accumulation. In contrast, higher levels of 210Pb2+ did not favor 210Pb uptake. For both metals, higher uptake data were recorded in the presence of SO4(2-), leading to sulfocomplex formation, compared with Cl-. Reciprocal inhibitions were minimal at high-cation levels but were significant and comparable in the presence of sulfo-complexes. We conclude that, in addition to Cd2+ (but not Pb2+), sulfocomplexes of both metals would preferentially be taken up compared to chlorocomplexes. NRAMP2 is not involved in Pb2+ uptake, and the NRAMP2-mediated Cd2+ uptake is insensitive to Pb. Uptake of Pb chlorocomplexes could involve specific mechanisms but of very low affinity, whereas uptake of Pb sulfocomplexes occurs with high affinity.

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Cadmium transport by human Nramp 2 expressed in Xenopus laevis oocytes

Cited by 64 publications

References 19 publications

Identification of mouse SLC39A8 as the transporter responsible for cadmium-induced toxicity in the testis

Identification of mouse SLC39A8 as the transporter responsible for cadmium-induced toxicity in the testis

Molecular and ionic mimicry and the transport of toxic metals

Reciprocal inhibition of Cd and Pb sulfocomplexes for uptake in Caco‐2 cells

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