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 three- to fourfold increase in the mRNA encoding the catalytically active heavy subunit of gamma-glutamylcysteine synthetase (GCS), the rate-limiting enzyme in GSH synthesis. In the present studies, we demonstrate that enhanced expression of GCS mRNA and GSH synthesis rapidly occur following acute MMH treatment and, moreover, that increased expression of renal GCS mRNA is localized predominantly to regions of the kidney 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 ability to up-regulate GSH synthesis subsequent to intracellular dealkylation of MMH to Hg2+. The present finding that GCS mRNA and GSH levels are rapidly increased in kidney cells which are most susceptible to mercury toxicity supports the view that up-regulation of GSH synthesis occurs as an initial adaptive response to Hg2(+)-mediated cytotoxicity following acute as well as prolonged mercury exposure.