LOCALIZATION BY IN-SITU HYBRIDIZATION OF GAMMA-GLUTAMYLCYSTEINE SYNTHETASE MESSENGER-RNA EXPRESSION IN RAT-KIDNEY FOLLOWING ACUTE METHYLMERCURY TREATMENT

In previous studies we reported that prolonged treatment of rats with subtoxic levels of mercury as methylmercury hydroxide (MMH) elicited a two- to threefold increase in renal glutathione (GSH) content and a t hree- to fourfold increase in the mRNA encoding the catalytically acti ve heavy subunit of gamma-glutamylcysteine synthetase (GCS), the rate- limiting enzyme in GSH synthesis. In the present studies, we demonstra te that enhanced expression of GCS mRNA and GSH synthesis rapidly occu r following acute MMH treatment and, moreover, that increased expressi on of renal GCS mRNA is localized predominantly to regions of the kidn ey cortex consistent with the principal distribution of mercury in the kidney. Previous studies have demonstrated that resistance to mercury toxicity during prolonged MMH exposure may be associated with the abi lity to up-regulate GSH synthesis subsequent to intracellular dealkyla tion of MMH to Hg2+. The present finding that GCS mRNA and GSH levels are rapidly increased in kidney cells which are most susceptible to me rcury toxicity supports the view that up-regulation of GSH synthesis o ccurs as an initial adaptive response to Hg2+-mediated cytotoxicity fo llowing acute as well as prolonged mercury exposure. (C) 1996 Academic Press, Inc.