In vivo inhibition of gamma-glutamylcysteine synthetase by L-methionine-RS-sulfoximine; influence on intermediates of the gamma-glutamyl cycle.

Abstract

Abstract—The inhibition of γ‐glutamylcysteine synthetase and its influence on the concentration of intermediates associated with the metabolism of glutathione was studied in mice receiving methionine sulfoximine, a convulsant agent. The activity of the enzyme decreased significantly in the liver and kidney 1‐4 h after administration of methionine sulfoximine; the activity of the enzyme in the brain was unchanged after 1 and 2 h but decreased significantly after 4 h. There was a rapid and sharp decrease in the concentration of glutathione in the kidney and a slower decrease in the liver. Brain glutathione concentrations were unaffected. Methionine sulfoximine in vivo, inhibited the synthesis of l‐γ‐glutamyl‐l‐α‐aminobutyrate after administration of l‐α‐aminobutyrate, a reaction catalyzed by γ‐glutamylcysteine synthetase. The inhibitor also lowered the concentration of pyrrolidone carboxylate in mouse tissues and prevented the accumulation of this intermediate after administration of l‐α‐aminobutyrate. The results show that methionine sulfoximine in vivo affects the metabolism of glutathione and that this action may contribute to its convulsive properties.