Prediction of Nephrotoxicant Action and Identification of Candidate Toxicity-Related Biomarkers

A vast majority of pharmacological compounds and their metabolites are excreted via the urine, and within the complex structure of the kidney, the proximal tubules are a main target site of nephrotoxic compounds. We used the model nephrotoxicants mercuric chloride, 2-bromoethylamine hydrobromide, hexachlorobutadiene, mitomycin, amphotericin, and puromycin to elucidate time- and dose-dependent global gene expression changes associated with proximal tubular toxicity. Male Sprague–Dawley rats were dosed via intraperitoneal injection once daily for mercuric chloride and amphotericin (up to 7 doses), while a single dose was given for all other compounds. Animals were exposed to 2 different doses of these compounds and kidney tissues were collected on day 1, 3, and 7 postdosing. Gene expression profiles were generated from kidney RNA using 17K rat cDNA dual dye microarray and analyzed in conjunction with histopathology. Analysis of gene expression profiles showed that the profiles clustered based on similaritie...