Basolateral Uptake of Inorganic Mercury in the Kidney

Zalups, Rudolfs K.

doi:10.1006/taap.1998.8416

Cited by 40 publications

(44 citation statements)

References 14 publications

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“…Moreover, both luminal and basolateral mechanisms have been shown to be involved in the proximal tubular transport and handling of inorganic mercuric ions (Zalups, 1995(Zalups, , 1997(Zalups, , 1998aZalups and Barfuss, 1995, 1998a,b, 2002Zalups and Minor, 1995;Zalups and Lash, 1997;Zalups et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…Various sets of data have recently implicated the formation of mercuric conjugates of Cys, N-acetylcysteine (NAC), and GSH in the proximal tubular transport of inorganic and organic forms of mercury (Zalups, 1995(Zalups, , 1998aAslamkhan et al, 2003;. Unfortunately, little attention has been paid to Hcy as a biologically relevant binding ligand of mercuric ions.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

mentioning

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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“…Recent studies provide strong evidence indicating that there are at least two distinct mechanisms (or sets of mechanisms) responsible for the uptake of Hg in proximal tubular cells: at least one localized in the luminal membrane Zalups, 1995Zalups, , 1997Zalups, , 1998aZalups, , 1998bBarfuss, 1993b, 1998a;Zalups and Minor, 1995;Zalups and Lash, 1997b;Zalups et al, 1991Zalups et al, , 1998 and at least another one in the basolateral membrane (Aslamkhan et al, 2003;Zalups, 1995Zalups, , 1997Zalups, , 1998aZalups and Barfuss, 1993b, 1998aZalups and Lash, 1997b;Zalups and Minor, 1995;.…”

Section: Molecular Mimicry and The Renal Transport Of Hg 2+mentioning

confidence: 99%

“…In addition to the uptake of Hg 2+ at the luminal plasma membrane, a preponderance of evidence indicates that approximately 40−60% of the proximal tubular uptake of Hg 2+ occurs via one or more transporters located at the basolateral membrane (Zalups, 1995(Zalups, , 1997(Zalups, , 1998a(Zalups, , 1998bZalups and Barfuss, 1995, 1998a, 1998bZalups and Minor, 1995). In experiments where the rates of glomerular filtration in rats were reduced to negligible levels, a 40% decrease in the renal tubular uptake of Hg 2+ was observed, indicating that the basolateral uptake of Hg 2+ comprises a significant fraction of the total renal uptake of Hg 2+ (Zalups and Minor, 1995).…”

Section: Molecular Mimicry and The Renal Transport Of Hg 2+mentioning

confidence: 99%

“…Both of these transporters are localized in the basolateral plasma membrane of proximal tubular epithelial cells (Kojima et al, 2002;Motohashi et al, 2002). The preponderance of current evidence indicates that OAT1 is the major mechanism for the uptake of Hg 2+ at the basolateral plasma membrane of proximal tubular cells (Zalups, 1995(Zalups, , 1997(Zalups, , 1998a(Zalups, , 1998bZalups and Barfuss, 1995, 1998a, 1998bZalups and Lash, 1994;Zalups et al, 1998).…”

Section: Molecular Mimicry and The Renal Transport Of Hg 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

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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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