© 1998 Oxford University Press
Effects of Lead on Glutathione S-Transferase Expression in Rat Kidney: A Dose—Response Study
Lynda S. Wright*,
Steven E. Kornguth*,
,
,
Terry D. Oberley
,|| and
Frank L. Siegel*,,¶,1
*The Waisman Center, University of Wisconsin Madison, Wisconsin 53705
Department of Biomolecular Chemistry, University of Wisconsin Madison, Wisconsin 53705
Department of Neurology, University of Wisconsin Madison, Wisconsin 53705
Department of Pathology and Laboratory Medicine University of Wisconsin Madison, Wisconsin 53705
||William S. Middleton Memorial Veteran's Hospital Madison, Wisconsin
¶Department of Pediatrics, University of Wisconsin Madison, Wisconsin 53705
Received May 20, 1998;
accepted July 8, 1998
Glutathione S-transferases (GST, EC 2.5.1.18) are a family of phase II detoxification enzymes involved in the conjugation of glutathione to a highly diverse group of compounds. The purpose of this study was to evaluate the dose-response effects of lead acetate administration on the expression of rat kidney GST. Sprague—Dawley rats were injected with doses of lead acetate ranging from 0.11 to 114 mg/kg (0.3 to 300 µmol/kg) for three consecutive days and sacrificed 24 h later. Kidney GST activity, GST isoform HPLC profiles, blood lead analysis, and electron microscopy were performed. A dose of 1.1 mg/kg lead acetate resulted in a blood lead level of 26 µg/dl and produced a significant increase in GST activity which continued to increase with dose up to 38 mg/kg. Morphological changes were detected at 3.8 mg/kg and increasing severity of cellular damage paralleled dose, blood lead levels, and changes in body weight. Individual GST isoforms exhibited different thresholds and maxima; rGSTP1 and rGSTM1 had thresholds of 1.1 and 3.8 mg/kg, respectively, very similar rates of increase with dose, and a maximum yield that was 450% above control at a dose of 38 mg/kg for both enzymes. rGSTA1 and rGSTA3 showed similar thresholds (1.1 mg/kg) and maximal fold increase (275%) but varied in the relative response to each dose. These results indicate that renal GST increases occur at lead levels which are environmentally significant, that these changes precede cellular damage, and suggest that GST may serve as a tissue biomarker of lead exposure.
Key Words: rat; kidney; glutathione S-transferase; lead; HPLC.
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