Methylmercury uptake in rat primary astrocyte cultures: the role of the neutral amino acid transport system

Aschner, Michael; Eberle, Nancy; Goderie, Susan K.; Kimelberg, Harold K.

doi:10.1016/0006-8993(90)91546-s

Cited by 89 publications

(49 citation statements)

References 29 publications

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“…It is noteworthy to mention that molecular mimicry has been suggested to be involved in the uptake of Cys S-conjugates of CH 3 Hg ϩ in glial and endothelial cells (Aschner et al, 1990(Aschner et al, , 1991Kerper et al, 1992;Clarkson, 1993;Mokrzan et al, 1995). CH 3 Hg-S-Cys has been hypothesized to serve as a molecular mimic of the amino acid methionine at one or more neutral amino acid transporters (Clarkson, 1993).…”

Section: Discussionmentioning

confidence: 99%

Transport ofN-AcetylcysteineS-Conjugates of Methylmercury in Madin-Darby Canine Kidney Cells Stably Transfected with Human Isoform of Organic Anion Transporter 1

Zalups¹,

Ahmad²

2005

J Pharmacol Exp Ther

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Recent studies have implicated the activity of the organic anion transporter 1 (OAT1) protein in the basolateral uptake of inorganic mercuric species in renal proximal tubular epithelial cells. However, very little is known about the potential role of OAT1 (and other OATs) in the renal epithelial transport of organic forms of mercury such as methylmercury (CH 3 Hg ϩ ). The present investigation was designed to study the transport of N-acetyl cysteine (NAC) S-conjugates of both methylmercury (CH 3 Hg-NAC) and inorganic mercury (NAC-Hg-NAC) in renal epithelial cells [Madin-Darby canine kidney (MDCK) cells] stably transfected with the human isoform of OAT1 (hOAT1). These mercuric species were studied because numerous mercapturates have been shown to be substrates of OATs. Data on saturation kinetics, time dependence, substrate specificity, and temperature dependence for the transport of CH 3 Hg-NAC and NAC-Hg-NAC indicate that both of these two mercuric species are indeed transportable substrates of hOAT1. Substrate specificity data also show that CH 3 Hg-NAC is a substrate of a transporter in MDCK cells that is not hOAT1. These data indicate that an amino acid carrier system is a likely candidate responsible for this transport. Furthermore, the rates of survival of the hOAT1-transfected MDCK cells were significantly lower than those of corresponding control MDCK cells when they were exposed to cytotoxic concentrations of CH 3 Hg-NAC or NAC-Hg-NAC. Collectively, the present data support the hypothesis that CH 3 Hg-NAC and NAC-Hg-NAC are transportable substrates of OAT1 and thus potentially transportable mercuric species taken up in vivo at the basolateral membrane of proximal tubular epithelial cells.

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Section: Discussionmentioning

confidence: 99%

Transport ofN-AcetylcysteineS-Conjugates of Methylmercury in Madin-Darby Canine Kidney Cells Stably Transfected with Human Isoform of Organic Anion Transporter 1

Zalups¹,

Ahmad²

2005

J Pharmacol Exp Ther

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“…It is noteworthy to mention that molecular mimicry has been suggested to be a potential mechanism involved in the uptake of the Cys S-conjugate of CH 3 Hg ϩ in glial and endothelial cells (Aschner et al, 1990(Aschner et al, , 1991Kerper et al, 1992;Clarkson, 1993;Mokrzan et al, 1995). It has been suggested that CH 3 Hg-S-Cys serves as a molecular mimic of the amino acid methionine at one or more neutral amino acid transporters (Clarkson, 1993).…”

Section: Discussionmentioning

confidence: 99%

Handling of the HomocysteineS-Conjugate of Methylmercury by Renal Epithelial Cells: Role of Organic Anion Transporter 1 and Amino Acid Transporters

Zalups¹,

Ahmad²

2005

J Pharmacol Exp Ther

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Recently, the activity of the organic anion transporter 1 (OAT1) protein has been implicated in the basolateral uptake of inorganic mercuric species in renal proximal tubular cells. Unfortunately, very little is known about the role of OAT1 in the renal epithelial transport of organic forms of mercury, such as methylmercury (CH 3 Hg ϩ ). Homocysteine (Hcy) S-conjugates of methylmercury [(S)-(3-amino-3-carboxypropylthio)(methyl)mercury (CH 3 Hg-Hcy)] have been identified recently as being potentially important biologically relevant forms of mercury. Thus, the present study was designed to characterize the transport of CH 3 Hg-Hcy in Madin-Darby canine kidney (MDCK) cells (which are derived from the distal nephron) that were transfected stably with the human isoform of OAT1 (hOAT1). Data on saturation kinetics, time dependence, substrate specificity, and temperature dependence demonstrated that CH 3 Hg-Hcy is a transportable substrate of hOAT1. However, substrate-specificity data from the control MDCK cells also showed that CH 3 Hg-Hcy is a substrate of one or more transporter(s) that is/are not hOAT1. Additional findings indicated that at least one amino acid transport system was probably responsible for this transport. It is noteworthy that the activity of amino acid transporters accounted for the greatest level of uptake of CH 3 HgHcy in the hOAT1-expressing cells. Furthermore, rates of survival of the hOAT1-transfected MDCK cells were significantly lower than those of corresponding control MDCK cells when they were exposed to cytotoxic concentrations of CH 3 Hg-Hcy. Collectively, the present data indicate that CH 3 Hg-Hcy is a transportable substrate of OAT1 and amino acid transporters and, thus, is probably a transportable mercuric species taken up in vivo by proximal tubular epithelial cells.Homocysteine (Hcy) is a sulfhydryl-containing amino acid formed from methionine after it undergoes demethylation. After its formation, Hcy is broken down by one of two mechanisms: remethylation or transsulfuration. In the remethylation pathway, a methyl group (from N 5 -methyltetrahydrofolate or betaine) is transferred to Hcy to re-form Met. In the alternative pathway, Hcy is converted to cysteine and ␣-ketobutyrate by trans-sulfuration, which requires the sequential actions of cystathionine-␤-synthase and ␥-cystathionase (Selhub, 1999).In blood, Hcy, Cys, and glutathione (GSH) make up a very important pool of nonprotein thiols to which various electrophiles, including metals such as mercury (Hg) and cadmium (Cd), can interact. Normal plasma levels of Hcy are generally similar to those of Cys and GSH (Lash and Jones, 1985). However, under certain pathophysiological conditions, the plasma levels of Hcy can increase from approximately 5 to 10 M to as much as 200 M (Stabler et al., 1988;Malinow, 1990;Selhub, 1999). Hyperhomocysteinemia is a significant clinical problem (resulting from altered intracellular metabolism of Hcy or Met) that has been implicated as a risk factor in the development of cardiovascular diseas...

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“…In addition, this transporter has a broad substrate-specificity (Oldendorf, 1973), which may allow it to utilize CH 3 Hg-S-Cys as a substrate. Indeed, in vivo studies in rats (Kerper et al, 1992) and in vitro studies utilizing primary cultures of rat astrocytes (Aschner et al, 1990(Aschner et al, , 1991 provided evidence that CH 3 Hg-S-Cys is a transportable substrate of system L. The involvement of this transporter in the uptake of CH 3 Hg-S-Cys was also demonstrated in another study utilizing cultured endothelial cells from the brain (Mokrzan et al, 1995). Interestingly, this study measured the uptake of CH 3 Hg + , as a conjugate of Hcy (CH 3 Hg-S-Hcy), or as CH 3 Hg-S-Cys and found that these two complexes were transported similarly.…”

Section: Molecular Mimicry and The Transport Of Ch 3 Hg + In Brainmentioning

confidence: 92%

“…The exact species of CH 3 Hg + that was transported was not determined in this study, nor was there direct evidence supporting the conclusion that system L was involved in this transport. However, since system L has been shown to mediate the transport of CH 3 Hg-S-Cys across the epithelial cells of and the astrocytes associated with the blood-brain barrier (Aschner et al, 1990;Kerper et al, 1992;Mokrzan et al, 1995), it is feasible that this same carrier is also responsible for the uptake of CH 3 Hg-S-Cys in placenta. System L has been identified in the placenta (Kanai et al, 1998;Pineda et al, 1999;Prasad et al, 1999) and is an important participant in the transfer of nutrients from the maternal to the fetal circulation.…”

Section: Molecular Mimicry and The Transport Of Ch 3 Hg + In Placentamentioning

confidence: 99%

Molecular and ionic mimicry and the transport of toxic metals

Bridges

Zalups

2005

Toxicology and Applied Pharmacology

665

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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Methylmercury uptake in rat primary astrocyte cultures: the role of the neutral amino acid transport system

Cited by 89 publications

References 29 publications

Transport ofN-AcetylcysteineS-Conjugates of Methylmercury in Madin-Darby Canine Kidney Cells Stably Transfected with Human Isoform of Organic Anion Transporter 1

Transport ofN-AcetylcysteineS-Conjugates of Methylmercury in Madin-Darby Canine Kidney Cells Stably Transfected with Human Isoform of Organic Anion Transporter 1

Handling of the HomocysteineS-Conjugate of Methylmercury by Renal Epithelial Cells: Role of Organic Anion Transporter 1 and Amino Acid Transporters

Molecular and ionic mimicry and the transport of toxic metals

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