Many naturally occurring and synthetic environmental toxicants, as well as, chemicals of agricultural importance, drugs and plant constituents of very diverse chemical structure share the ability to induce relatively specific injury to the renal proximal tubule of animals and humans. Utilizing at least 7 different classes of nephrotoxins our specific aims are fourfold: First, we plan to continue to demonstrate that the dog is an excellent species in which to investigate the nephrotoxicity of chemicals if the results are to be projected to the human setting. Second, using the dog we plan to continue to quantitatively and simultaneously delineate the acute effects (i.e., over periods of 2,5,12, and 24 hours) of the 7 classes of neophrotoxins on 9 whole blood/plasma parameters, 12 renal function parameters and on the ultrastructure of all 10 cell types that line the dog nephron. Third, we have proposed a mechanism for chemical-induced nephrotoxicity into which all 7 classes of nephrotoxins fit. The mechanism involves at least two steps, and requires that each nephrotoxin possess two important structural (chemical) features: (1) a weakly acidic or an amino acid moiety that allows for the specific proximal tubular uptake of the chemical, and (2) a moiety that can either directly alkylate renal tissue or be converted in vivo to such a substance. This mechanistic model for chemical-induced proximal tubular necrosis will continue to be tested by (a) attempting to modify the renal toxicity of chemicals by pretreating dogs with probenecid which competitively inhibits the proximal tubular uptake of weakly acidic chemicals, or with N-acetyl-L-cysteine which will scavenge chemicals with alkylating properties, (b) synthesizing and testing the renal actions of non-alkylating derivatives of all 7 classes of toxins, and (c) determining the role of biotransformation in the renal toxicity of certain toxins. Fourth, we plan to continue to determine the role of the renal Gamma-glutamyl cycle in modulating the renal toxicity of chemicals. Accomplishing these four specific aims will lead to: a better understanding of the biochemical mechanism by which many chemicals in our environment induce relatively specific injury to the renal proximal tubule, the synthesis of safer drugs, ways of modifying the toxicity of existing drugs and chemicals, and a means for the early detection of chemical-induced renal damage.
