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 (CH3Hg+) were evaluated in isolated, perfused rabbit proximal tubular segments. When these conjugates were perfused individually through the lumen of S2 segments of the proximal tubule it was found that Cys-S-CH3Hg and GSH-S-CH3Hg were transported avidly, while NAC-S-CH3Hg was transported minimally. In addition, 95% of the 203Hg 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-CH3Hg was temperature-dependent and inhibited significantly by the amino acids l-methionine and l-cystine. Rates of luminal uptake of GSH-S-CH3Hg were twice as great as that of Cys-S-CH3Hg 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-CH3Hg was diminished significantly. Overall, our data indicate that Cys-S-CH3Hg is likely a transportable substrate of one or more amino acid transporters (such as system B0,+ and system b0,+) involved in luminal absorption of l-methionine and l-cystine along the renal proximal tubule. In addition, GSH-S-CH3Hg appears to be degraded enzymatically to Cys-S-CH3Hg, which can then be taken up at the luminal membrane. By contrast NAC-S-CH3Hg and Cys-S-CH3Hg (in the presence of DMPS) are not taken up avidly at the luminal membrane of proximal tubular cells, thus promoting the excretion of CH3Hg+ into the urine.