gamma-Glutamyl transpeptidase and l-cysteine regulate methylmercury uptake by HepG2 cells, a human hepatoma cell line.
Mechanisms of methylmercury (MeHg) and inorganic mercury (Hg) uptake were examined in HepG2 cells, a human hepatoma-derived cell line. MeHg uptake was faster when it was present as the l-cysteine complex, as compared to the glutathione (GSH), CysGly, gamma-GluCys, d-cysteine, N-acetylcysteine, l-penicillamine, or albumin complexes. Uptake of MeHg-l-cysteine was independent of Na(+), stereoselective, and was inhibited by the amino acid transport system l substrates l-leucine, l-valine, and l-phenylalanine (5 mM). Moreover, [(3)H]l-leucine uptake was inhibited by MeHg-l-cysteine, suggesting that MeHg-l-cysteine is transported into HepG2 cells by an l-type amino acid carrier. Uptake of MeHg as the GSH complex (MeHg-SG) was dependent on the extracellular GSH concentration, and was diminished when cellular gamma-glutamyl transpeptidase activity was inhibited. Inorganic mercury uptake was slower than that of MeHg, but was also sensitive to the type of thiol ligand present. These findings demonstrate that mercury uptake by HepG2 cells is dependent on the chemical structure of the mercury compound, the thiol ligand, and the activity of gamma-glutamyl transpeptidase. gamma-Glutamyl transpeptidase appears to play a key role in the disposition of MeHg-SG by facilitating the formation of MeHg-l-cysteine, which is readily transported into the cells on an amino acid-type carrier.
Wang
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W
Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, New York 14642, USA.
Clarkson
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TW
Ballatori
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N
D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003545:Cysteine / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism; D008628:Mercury / Q000493:pharmacokinetics; D008767:Methylmercury Compounds / Q000493:pharmacokinetics*; D014407:Tumor Cells, Cultured; D005723:gamma-Glutamyltransferase / Q000502:physiology*
D008767:Methylmercury Compounds; D005723:gamma-Glutamyltransferase; D008628:Mercury; D003545:Cysteine