Effect of DMT1 knockdown on iron, cadmium,  and lead uptake in Caco-2 cells

Bannon, Desmond I.; Abounader, Roger; Lees, Peter S.J.; Bressler, Joseph

doi:10.1152/ajpcell.00184.2002

Cited by 204 publications

(135 citation statements)

References 29 publications

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“…These data provide strong evidence supporting the hypothesis that DMT1 mediates the intestinal uptake of Cd 2+ . Additional studies in Caco-2 cells corroborated the aforementioned findings (Bannon et al, 2003). Stable transfection of Caco-2 cells with an antisense construct of DMT1 successfully "knocked down" the activity of DMT1 in these cells.…”

Section: Mimicry and Intestinal Transport Of CD 2+supporting

confidence: 65%

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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Section: Mimicry and Intestinal Transport Of CD 2+supporting

confidence: 65%

Molecular and ionic mimicry and the transport of toxic metals

Bridges

Zalups

2005

Toxicology and Applied Pharmacology

676

460

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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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“…Evidence for the effect for iron deficiency on lead absorption has been provided from animal studies. In rats, iron deficiency increases the gastrointestinal absorption of lead, possibly by enhancing binding of lead to iron binding proteins in the intestine (Bannon et al 2003;Barton et al 1978b;Morrison and Quaterman 1987) (see Section 3.4.1 for further discussion).…”

Section: Effect Of Nutritionmentioning

confidence: 99%

“…When mRNA for DMT1, a mucosal membrane carrier for iron, was suppressed in Caco 2 cells (a human gastrointestinal cell line) the rate of iron and cadmium uptake decreased by 50% compared to cells in which DMT1 mRNA was not suppressed; however, DMT1 mRNA suppression did not alter the rate of lead uptake by Caco 2 cells, indicating that lead may enter Caco 2 cells through a mechanism that is independent of DMT1 (Bannon et al 2003). The above observations suggest that ratelimiting saturable mechanisms for lead absorption are associated with transfer of lead from cell to blood rather than with mucosal transfer.…”

Section: Pharmacokinetic Mechanisms Absorptionmentioning

confidence: 99%