Renal Glutathione and Mercury Uptake by Kidney

Berndt, William O.; Baggett, J.McC.; Blacker, Ann M.; Houser, Mark T.

doi:10.1093/toxsci/5.5.832

Cited by 17 publications

(25 citation statements)

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“…Experimental evidence supporting the role of γ-glutamyltransferase in the renal tubular uptake of CH 3 Hg + comes from studies in which the activity of this enzyme was inhibited by the alkylating agent acivicin. Following the pretreatment with acivicin, the renal tubular uptake of CH 3 Hg + was shown to decrease while the urinary excretion of GSH and CH 3 Hg + was shown to increase (Bernt et al, 1985;de Ceaurriz and Ban, 1990;DiSimplicio et al, 1990;Gregus et al, 1987;Mulder and Kostyniak, 1985;Naganuma et al, 1988;Tanaka et al, 1990Tanaka et al, , 1991Tanaka et al, , 1992. The observed changes in the renal cellular uptake and excretion of CH 3 Hg + indicate that the catabolism of the CH 3 Hg-S-G complex is a necessary step in the renal proximal tubular absorption of CH 3 Hg + .…”

Section: Molecular Mimicry and The Renal Transport Of Ch 3 Hg +mentioning

confidence: 98%

“…Numerous in vivo experiments have demonstrated that inhibition of γ-glutamyltransferase with acivicin (an irreversible alkylating agent of γ-glutamyltransferase) reduces significantly the renal (proximal) tubular uptake and accumulation of systemically administered Hg 2+ (Bernt et al, 1985;de Ceaurriz et al, 1994;Tanaka et al, 1990;Tanaka-Kagawa et al, 1993;Zalups, 1995). These studies led to the hypothesis that GSH S-conjugates of Hg 2+ (G-S-Hg-S-G), entering the luminal compartment of the proximal tubule, are degraded rapidly and efficiently by γ-glutamyltransferase and cysteinylglycinase to yield thiol S-conjugates of Hg 2+ , including Cys S-conjugates of Hg 2+ (Cys-S-Hg-S-Cys).…”

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

667

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: Molecular Mimicry and The Renal Transport Of Ch 3 Hg +mentioning

confidence: 98%

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

confidence: 99%

Molecular and ionic mimicry and the transport of toxic metals

Bridges

Zalups

2005

Toxicology and Applied Pharmacology

667

460

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“…It seems that mercuric conjugates of GSH, while in the lumen of the proximal tubule, are degraded sequentially by these enzymes to yield a cysteine-S-conjugate of mercury, primarily 2-amino-3-(2-amino-2-carboxyethylsulfanylmercuricsulfanyl)propionic acid (Cys-S-Hg-S-Cys) (2). This conjugate is thought to be the principal species of Hg 2ϩ taken up at the luminal plasma membrane of proximal tubular epithelial cells (3)(4)(5)(6)(7)(8).…”

mentioning

confidence: 99%

Mercuric Conjugates of Cysteine Are Transported by the Amino Acid Transporter System b0,+

Bridges¹,

Bauch²,

Verrey³

et al. 2004

Journal of the American Society of Nephrology

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Abstract. Humans and other mammals continue to be exposed to various forms of mercury in the environment. The kidneys, specifically the epithelial cells lining the proximal tubules, are the primary targets where mercuric ions accumulate and exert their toxic effects. Although the actual mechanisms involved in the transport of mercuric ions along the proximal tubule have not been defined, current evidence implicates mercuric conjugates of cysteine, primarily 2-amino-3-(2-amino-2-carboxyethylsulfanylmercuricsulfanyl)propionic acid (Cys-S-Hg-S-Cys), as the most likely transportable species of inorganic mercury (Hg 2ϩ ). Because Cys-S-Hg-S-Cys and the amino acid cystine (Cys-S-S-Cys) are structurally similar, it was hypothesized that Cys-S-Hg-S-Cys might act as a molecular mimic of cystine at one or more of the amino acid transporters involved in the luminal absorption of this amino acid. One such candidate is the Na ϩ -independent heterodimeric transporter system b 0,ϩ . Therefore, the transport of Cys-S-Hg-S-Cys and cystine was studied in MDCK II cells that were or were not stably transfected with b 0,ϩ AT-rBAT. Transport of Cys-S-Hg-S-Cys and cystine across the luminal plasma membrane was similar in the transfected cells, indicating that Cys-S-Hg-S-Cys can behave as a molecular mimic of cystine at the site of system b 0,ϩ . Moreover, only the b 0,ϩ AT-rBAT transfectants became selectively intoxicated during exposure to Cys-S-Hg-S-Cys. These findings indicate that system b 0,ϩ likely contributes to the nephropathy induced by Hg 2ϩ in vivo. These data represent the first direct molecular evidence for the participation of a specific transporter in the luminal uptake of a large divalent metal cation in proximal tubular cells.A large body of evidence indicates that the epithelial cells lining the convoluted and straight segments of the proximal tubule are the primary sites where inorganic mercury (Hg 2ϩ ) is taken up and accumulated in vivo (1,2). Although the actual mechanisms by which mercuric ions are taken up by these cells are not well defined, a number of recent in vivo findings indicate that the uptake of Hg 2ϩ at the luminal membrane of proximal tubular cells is dependent on the activities of the brush border enzymes ␥-glutamyltransferase (3-8) and cysteinylglycinase (8). It seems that mercuric conjugates of GSH, while in the lumen of the proximal tubule, are degraded sequentially by these enzymes to yield a cysteine-S-conjugate of mercury, primarily 2-amino-3-(2-amino-2-carboxyethylsulfanylmercuricsulfanyl)propionic acid (Cys-S-Hg-S-Cys) (2). This conjugate is thought to be the principal species of Hg 2ϩ taken up at the luminal plasma membrane of proximal tubular epithelial cells (3-8).Recent studies using brush border membrane vesicles (9) and isolated perfused proximal tubular segments (8,10) indicate that Cys-S-Hg-S-Cys is indeed transported across the luminal membrane of proximal tubular epithelial cells. Moreover, competitive inhibition experiments using isolated perfused proximal tubular segments have i...

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“…Both protein and non-protein sulfhydryl-containing compounds bind Hg 2+ with high affinity and are the major ligands for Hg 2+ in both the extracellular and intracellular space (Zalups and Lash, 1994). The cellular content of thiols, particularly that of glutathione (GSH), can modulate the intracellular uptake, cellular accumulation, and toxicity of Hg 2+ in the renal proximal tubule (Baggett and Berndt, 1986;Berndt et al, 1985;Burton et al, 1995;de Ceaurriz et al, 1994;Girardi and Elias, 1993;Lash et al, 1998aLash et al, ,1999aZalups and Lash, 1997). Conversely, prior exposure of rats to Hg 2+ alters cellular GSH status, with subtoxic concentrations increasing and toxic concentrations depleting GSH concentrations in the cortex and outer stripe of the outer medulla (Lash and Zalups, 1996;Zalups and Lash, 1990).…”

Section: Introductionmentioning

confidence: 99%

Interactive toxicity of inorganic mercury and trichloroethylene in rat and human proximal tubules: Effects on apoptosis, necrosis, and glutathione status

Lash

Putt

Hueni

et al. 2007

Toxicology and Applied Pharmacology

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Simultaneous or prior exposure to one chemical may alter the concurrent or subsequent response to another chemical, often in unexpected ways. This is particularly true when the two chemicals share common mechanisms of action. The present study uses the paradigm of prior exposure to study the interactive toxicity between inorganic mercury (Hg 2+ ) and trichloroethylene (TRI) or its metabolite S-(1,2-dichlorovinyl)-L-cysteine (DCVC) in rat and human proximal tubule. Pretreatment of rats with a subtoxic dose of Hg 2+ increased expression of glutathione S-transferase-α1 (GSTα1) but decreased expression of GSTα2, increased activities of several GSH-dependent enzymes, and increased GSH conjugation of TRI. Primary cultures of rat proximal tubular (rPT) cells exhibited both necrosis and apoptosis after incubation with Hg 2+ . Pretreatment of human proximal tubular (hPT) cells with Hg 2+ caused little or no changes in GST expression or activities of GSH-dependent enzymes, decreased apoptosis induced by TRI or DCVC, but increased necrosis induced by DCVC. In contrast, pretreatment of hPT cells with TRI or DCVC protected from Hg 2+ by decreasing necrosis and increasing apoptosis. Thus, whereas pretreatment of hPT cells with Hg 2+ exacerbated cellular injury due to TRI or DCVC by shifting the response from apoptosis to necrosis, pretreatment of hPT cells with either TRI or DCVC protected from Hg 2+ -induced cytotoxicity by shifting the response from necrosis to apoptosis. These results demonstrate that by altering processes related to GSH status, susceptibilities of rPT and hPT cells to acute injury from Hg 2+ , TRI, or DCVC are markedly altered by prior exposures.

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Renal Glutathione and Mercury Uptake by Kidney

Cited by 17 publications

References 0 publications

Molecular and ionic mimicry and the transport of toxic metals

Molecular and ionic mimicry and the transport of toxic metals

Mercuric Conjugates of Cysteine Are Transported by the Amino Acid Transporter System b0,+

Interactive toxicity of inorganic mercury and trichloroethylene in rat and human proximal tubules: Effects on apoptosis, necrosis, and glutathione status

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