The effects of cysteine (80 microM), glutathione (80 microM), rabbit albumin (100 microM), and an ultrafiltrate of rabbit plasma on the toxicity and transport of inorganic mercury (Hg2+; 18.4 microM) in isolated perfused S1, S2, and S3 segments of the renal proximal tubule from the rabbit were studied. Cellular and tubular injuries were assessed qualitatively by light microscopy observations and quantitatively by the tubular leak of the volume marker 3H-glucose. The lumen-to-bath transport of inorganic mercury was assessed by measuring both the rate of disappearance of inorganic mercury from the luminal fluid and the rate of appearance of inorganic mercury in the bath. When glutathione was added to the perfusate containing the inorganic mercury, no signs of epithelial cell necrosis or injury were detected in any of the three segments of the proximal tubule. There was also an absence of or a decrease in cellular injury in the epithelium of the same tubular segments when either cysteine or the ultrafiltrate was present in the perfusate. However, when rabbit albumin and inorganic mercury were present in the perfusate, severe degenerative and necrotic changes occurred very rapidly in the epithelium of all three segments of the proximal tubule. In almost every instance where glutathione, cysteine, or the plasma ultrafiltrate were present in the perfusate, the disappearance flux of inorganic mercury from the tubular lumen into the tubular epithelium was lowered. It was concluded that glutathione, cysteine, and the ultrafiltrate of rabbit plasma provide isolated perfused S1, S2, and S3 segments of the proximal tubule varying degrees of protection from the toxic effects of inorganic mercury. This protection appears to be related to a decrease in the movement of inorganic mercury across the luminal membrane of the tubular epithelial cells.