Intraperitoneal administration of lead acetate to male Sprague-Dawley rats resulted in the tissue-specific transcriptional activation of the microsomal epoxide hydrolase gene in kidney. This response was followed by a 15-fold increase in the level of kidney epoxide hydrolase mRNA, while no change in mRNA level was noted in liver. Treated animals also showed no increase in mRNA levels for NADPH-cytochrome P-450 oxidoreductase, cytochrome P-450b/e, cytochrome P-450PCN (where PCN is pregnenolone 16 alpha-carbonitrile), or serum albumin in either kidney or liver. Immunoquantitation of the enzyme revealed a 16-fold increase in kidney upon treatment with lead acetate, but significant changes in epoxide hydrolase levels were not noted in liver, heart, spleen, lung, small intestine, or testis. The enzymatic activity for liver and kidney paralleled the immunochemical results; however, the activity increase in kidney was only one-third of the increase noted for total enzyme protein. Immunohistochemical analysis of epoxide hydrolase protein in sections of rat kidney demonstrated that in lead acetate-treated animals there was a marked increase in staining of the cytoplasm of the proximal tubular cells in the outer cortex as compared with kidneys from control animals. In contrast, considerable protein was also localized to collecting ducts, but no change was evident in the content of the epoxide hydrolase gene product in these structures in control and lead acetate-treated animals. Immunohistochemical differences were not noted between livers from control and lead-treated animals. Furthermore, the staining patterns for NADPH-cytochrome P-450 oxidoreductase were the same for control and treated animals in both kidney and liver. Quantitative measurements of lead uptake by various rat tissues showed liver, spleen, and small intestine reaching a maximum of approximately 12,000 ng of lead/g of dry tissue at 8, 8, and 16 h, respectively, while kidney, lung, and testis peaked (approximately 3,000 ng of lead/g of dry tissue) at 16, 16, and 12 h, respectively.