Interactions of methylmercury with rat primary astrocyte cultures: methylmercury efflux

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

doi:10.1016/0006-8993(91)90165-r

Cited by 24 publications

(6 citation statements)

References 18 publications

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“…Before mercury can have an effect, it must first cross several barriers. Several studies support that MeHg-L-cysteine is transported across the blood–brain barrier by the L-type amino acid transporters used to transport neutral amino acids [18], as was first observed by Aschner et al, who observed competitive inhibition of MeHg uptake in astrocytes by large, neutral amino acids [19, 20]. …”

Section: Neurotoxicitymentioning

confidence: 83%

Recent Advances in Mercury Research

Martinez-Finley

Aschner

2014

Curr Envir Health Rpt

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Mercury (Hg) is a highly toxic, non-essential, naturally occurring metal with a variety of uses. Mercury is not required for any known biological process and its presence in the human body may be detrimental, especially to the nervous system. Both genetic and behavioral studies suggest that mercury levels, age (both of exposure and at testing), and genetic background determine disease processes and outcome. The metal receptors and genes responsible for mercury metabolism also appear to play a pivotal role in the etiology of mercury-induced pathology. This review presents information about the latest advances in mercury research, with particular focus on low-level exposures and the contribution of genetics to toxic outcome. Future studies should address the contribution of genetics and low-level mercury exposure to disease, namely gene x environment interactions, taking into consideration age of exposure as developing animals are exquisitely more sensitive to this metal. In addition to recent advances in understanding the pathology associated with mercury exposure, the review highlights transport mechanisms, cellular distribution and detoxification of mercury species in the body.

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Section: Neurotoxicitymentioning

confidence: 83%

Recent Advances in Mercury Research

Martinez-Finley

Aschner

2014

Curr Envir Health Rpt

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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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“…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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Interactions of methylmercury with rat primary astrocyte cultures: methylmercury efflux

Cited by 24 publications

References 18 publications

Recent Advances in Mercury Research

Recent Advances in Mercury Research

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

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