Luminal transport of thiol S-conjugates of methylmercury in isolated perfused rabbit renal proximal tubules.
Lumen-to-cell transport, cellular accumulation, and toxicity of L-cysteine (Cys), glutathione (GSH) and N-acetylcysteine (NAC) S-conjugates of methylmercury (CH(3)Hg(+)) were evaluated in isolated, perfused rabbit proximal tubular segments. When these conjugates were perfused individually through the lumen of S(2) segments of the proximal tubule it was found that Cys-S-CH(3)Hg and GSH-S-CH(3)Hg were transported avidly, while NAC-S-CH(3)Hg was transported minimally. In addition, 95% of the (203)Hg taken up by the tubular cells was associated with precipitable proteins of the tubule, while very little was found in the acid-soluble cytosol. No visual cellular pathological changes were observed during 30min of study. Luminal uptake of Cys-S-CH(3)Hg was temperature-dependent and inhibited significantly by the amino acids L-methionine and l-cystine. Rates of luminal uptake of GSH-S-CH(3)Hg were twice as great as that of Cys-S-CH(3)Hg and uptake was inhibited significantly (74%) by the presence of acivicin. When 2,3-bis(sulfanyl)propane-1-sulfonate (DMPS) was added to the bathing or luminal fluid, luminal uptake of Cys-S-CH(3)Hg was diminished significantly. Overall, our data indicate that Cys-S-CH(3)Hg is likely a transportable substrate of one or more amino acid transporters (such as system B(0,+) and system b(0,+)) involved in luminal absorption of L-methionine and L-cystine along the renal proximal tubule. In addition, GSH-S-CH(3)Hg appears to be degraded enzymatically to Cys-S-CH(3)Hg, which can then be taken up at the luminal membrane. By contrast NAC-S-CH(3)Hg and Cys-S-CH(3)Hg (in the presence of DMPS) are not taken up avidly at the luminal membrane of proximal tubular cells, thus promoting the excretion of CH(3)Hg(+) into the urine.
Department of Biology, Georgia State University, Atlanta, GA 30303, United States. ywang68@emory.edu
Yanhua
Y
Wang
Rudolfs K
RK
Zalups
Delon W
DW
Barfuss
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D000818:Animals; D001692:Biological Transport; D003545:Cysteine / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D005260:Female; D005978:Glutathione / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism*; D008767:Methylmercury Compounds / Q000493:pharmacokinetics*; D011817:Rabbits; D014494:Unithiol / Q000494:pharmacology
D007555:Isoxazoles; D008767:Methylmercury Compounds; D014494:Unithiol; D005978:Glutathione; D003545:Cysteine; C006303:acivicin; D000111:Acetylcysteine