Human Renal Organic Anion Transporter 1-Dependent Uptake and Toxicity of Mercuric-Thiol Conjugates in Madin-Darby Canine Kidney Cells

Aslamkhan, Amy G.; Han, Yong‐Hae; Yang, Xiao‐Ping; Zalups, Rudolfs K.; Pritchard, John B.

doi:10.1124/mol.63.3.590

Cited by 82 publications

(80 citation statements)

References 35 publications

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“…NAC-S-Hg-S-NAC is a highly polar homolog of Cys-S-Hg-S-Cys that is efficiently transported into proximal tubular epithelial cells from the basolateral extracellular compartment by one or more organic anion transporters (2,17). In the lumen, however, the negative charge on each end of the NAC-S-Hg-S-NAC complex is thought to impede or prevent absorption of this mercuric conjugate across the luminal plasma membrane of renal epithelial cells lining the nephron and collecting ducts.…”

Section: Discussionmentioning

confidence: 99%

“…The radioactivity of the solution was determined with a Perkin Elmer Wallac Wizard 3 automatic gamma counter (Perkin Elmer, Gaithersburg, MD). The specific activities of the 203 Hg ranged from 6 to 12 mCi/mg (17).…”

Section: Manufacture Of 203 Hg 2ϩmentioning

confidence: 99%

“…The toxicologic effects of HgCl 2 , Cys-S-Hg-S-Cys, and GSH-S-Hg-S-GSH were measured with a methylthiazoletetrazolium assay, as described previously (17). Wild-type and transfected MDCK cells were seeded at a density of 0.2 ϫ 10 6 cells/ml in 96-well culture dishes (200 l/well).…”

Section: Assessment Of Cellular Viabilitymentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Manufacture Of 203 Hg 2ϩmentioning

confidence: 99%

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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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“…For example, mercury exists in the blood in thiol conjugates (with glutathione and cystathione), which effectively act like organic anions. OAT1 and OAT3 appear to be the major transporters involved in elimination of mercuric conjugates, which can lead to renal and central nervous system toxicity following mercurial exposure (48)(49)(50)(51). The proximal tubule of the kidney of the Oat1 knockout mouse is largely resistant to nephrotoxic damage that occurs from systemic administration of mercuric chloride (Figure 3) (52).…”

Section: Drugs and Toxinsmentioning

confidence: 99%

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

Nigám¹,

Wu²,

Bush³

et al. 2015

Clinical Journal of the American Society of Nephrology

227

192

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The proximal tubule of the kidney plays a crucial role in the renal handling of drugs (e.g., diuretics), uremic toxins (e.g., indoxyl sulfate), environmental toxins (e.g., mercury, aristolochic acid), metabolites (e.g., uric acid), dietary compounds, and signaling molecules. This process is dependent on many multispecific transporters of the solute carrier (SLC) superfamily, including organic anion transporter (OAT) and organic cation transporter (OCT) subfamilies, and the ATP-binding cassette (ABC) superfamily. We review the basic physiology of these SLC and ABC transporters, many of which are often called drug transporters. With an emphasis on OAT1 (SLC22A6), the closely related OAT3 (SLC22A8), and OCT2 (SLC22A2), we explore the implications of recent in vitro, in vivo, and clinical data pertinent to the kidney. The analysis of murine knockouts has revealed a key role for these transporters in the renal handling not only of drugs and toxins but also of gut microbiome products, as well as liverderived phase 1 and phase 2 metabolites, including putative uremic toxins (among other molecules of metabolic and clinical importance). Functional activity of these transporters (and polymorphisms affecting it) plays a key role in drug handling and nephrotoxicity. These transporters may also play a role in remote sensing and signaling, as part of a versatile small molecule communication network operative throughout the body in normal and diseased states, such as AKI and CKD.

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“…This mixture was allowed to incubate at room temperature for at least 5 min. The 203 Hg 2+ (2.36 mCi/mg) was generated by neutron activation of 202 HgO at the Missouri University Research Reactor (Aslamkhan et al, 2003;Belanger et al, 2001). …”

Section: Evaluation Of Transportmentioning

confidence: 99%

Transport of thiol-conjugates of inorganic mercury in human retinal pigment epithelial cells

Bridges¹,

Battle²,

Zalups³

2007

Toxicology and Applied Pharmacology

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Inorganic mercury (Hg 2+ ) is a prevalent environmental contaminant to which exposure to can damage rod photoreceptor cells and compromise scotopic vision. The retinal pigment epithelium (RPE) likely plays a role in the ocular toxicity associated with Hg 2+ exposure in that it mediates transport of substances to the photoreceptor cells. In order for Hg 2+ to access photoreceptor cells, it must be first be taken up by the RPE, possibly by mechanisms involving transporters of essential nutrients. In other epithelia, Hg 2+ , when conjugated to cysteine (Cys) or homocysteine (Hcy), gains access to the intracellular compartment of the target cells via amino acid and organic anion transporters. Accordingly, the purpose of the current study was to test the hypothesis that Cys and Hcy S-conjugates of Hg 2+ utilize amino acid transporters to gain access into RPE cells. Time-and temperaturedependence, saturation kinetics, and substrate-specificity of the transport of Hg 2+ , was assessed in ARPE-19 cells exposed to the following S-conjugates of Hg 2+ : Cys (Cys-S-Hg-S-Cys), Hcy (Hcy- S-Hg-S-Hcy), N-acetylcysteine (NAC-S-Hg-S-NAC) or glutathione (GSH-S-Hg-S-GSH).We discovered that only Cys-S-Hg-S-Cys and Hcy-S-Hg-S-Hcy were taken up by these cells. This transport was Na + -dependent and was inhibited by neutral and cationic amino acids. RT-PCR analyses identified systems B 0,+ and ASC in ARPE-19 cells. Overall, our data suggest that Cys-SHg-S-Cys and Hcy-S-Hg-S-Hcy are taken up into ARPE-19 cells by Na-dependent amino acid transporters, possibly systems B 0,+ and ASC. These amino acid transporters may play a role in the retinal toxicity observed following exposure to mercury.

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Human Renal Organic Anion Transporter 1-Dependent Uptake and Toxicity of Mercuric-Thiol Conjugates in Madin-Darby Canine Kidney Cells

Cited by 82 publications

References 35 publications

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

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

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

Transport of thiol-conjugates of inorganic mercury in human retinal pigment epithelial cells

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