Sex hormone and developmental regulation of glutathione - S-transferase enzymes in rat liver and kidney

Abstract

Glutathione-S-transferases (E. C. 2.5.1.18) are multifunctional enzymes, widely dispersed among eukaryotic organisms, that are involved in detoxification, organic anion transport (including bilirubin), carcinogenesis and leukotriene biosynthesis. To understand the molecular basis of the differential regulation of glutathione-S-transferase isozyme forms during development and in response to sex hormones, we have examined their tissue specific expression using liver and kidney from male, female and ovariectomized rats. The relative distribution of various homodimeric and heterodimeric forms of GST's and their messenger RNA levels were determined by measuring catalytic activities with subunit specific substrates and by measuring the subunit composition of purified enzymes using SDS-PAGE. Subunit distribution was also monitored with polyclonal antibodies, using an ELISA assay. The distribution of messenger RNA was determined by Northern blot analysis using specific cDNA probes.;Livers from male rats had much higher proportions of GST isozymes containing subunits 3 and 4 than livers from females; in kidney, however, females had much higher amounts of these isozymes than males. Ovariectomy increased these GST forms in liver, and decreased them in kidney, to levels approximating male liver and kidney. The steady state messenger RNA levels for subunits 3 and 4 paralleled the levels of isozymes 3-3, 3-4, and 4-4 and their activities. Human kidney tissue was found to display similar sex-related differences in isozyme composition. During development in the rat, total GST activity increased in both the liver and kidney, as measured by immunoreactivity and mRNA levels. However, the rates of increase were different in the two tissues, and varied for particular isozymes when comparing male and female rats. The results suggest that there is a sex hormone dependent regulation of GST isozymes in liver and kidney during development.