Abstract

Glutathione transferase zeta (GSTZ1–1) catalyzes the biotransformation of a range of α-haloacids, including dichloroacetic acid (DCA), and the penultimate step in the tyrosine degradation pathway. DCA is a rodent carcinogen and a common drinking water contaminant. DCA also causes multiorgan toxicity in rodents and dogs. The objective of this study was to determine the expression and activities of GSTZ1–1 in rat tissues with maleylacetone and chlorofluoroacetic acid as substrates. GSTZ1–1 protein was detected in most tissues by immunoblot analysis after immunoprecipitation of GSTZ1–1 and by immunohistochemical analysis; intense staining was observed in the liver, testis, and prostate; moderate staining was observed in the brain, heart, pancreatic islets, adrenal medulla, and the epithelial lining of the gastrointestinal tract, airways, and bladder; and sparse staining was observed in the renal juxtaglomerular regions, skeletal muscle, and peripheral nerve tissue. These patterns of expression corresponded to GSTZ1–1 activities in the different tissues with maleylacetone and chlorofluoroacetic acid as substrates. Specific activities ranged from 258 ± 17 (liver) to 1.1 ± 0.4 (muscle) nmol/min/mg of protein with maleylacetone as substrate and from 4.6 ± 0.89 (liver) to 0.09 ± 0.01 (kidney) nmol/min/mg of protein with chlorofluoroacetic acid as substrate. Rats given DCA had reduced amounts of immunoreactive GSTZ1–1 protein and activities of GSTZ1–1 in most tissues, especially in the liver. These findings indicate that the DCA-induced inactivation of GSTZ1–1 in different tissues may result in multiorgan disorders that may be associated with perturbed tyrosine metabolism.