A Novel Physiological Role of Liver Glutathione as a Reservoir of L-Cysteine

1) To verify the presence of more than one pool of glutathione in the liver, a diet containing L-[35S] cysteine was given to rats, and after chasing and exhaustion of the 35S-label a second diet containing L[3,3-3H] cystiene was given. Starvation of the rats thus treated revealed differential decay of 35S and 3H incorporated into liver glutathione: 3H incorporated later into glutathione disappeared rapidly on starvation, while a large portion of 35S incorporated earlier and remaining in the glutathione did not. A concomitant increase in 3H-label of hepatic proteins on starvation indicated that cysteine derived from glutathione was probably incorporated into proteins. 2) Analysis of the decay curve of the 35S-labeled cysteine moiety of liver glutathione under normal feeding conditions revealed at least two types of glutathione with different biological half-lives. The apparent half-lives were 1.7 and 28.5 h. Precipitous decay of glutathione-35S in the initial phase of starvation was accompanied by a rise of incorporation of 35S into proteins. 3) To prove mobilization of cysteine moiety of liver glutathione, a gelatin-diet containing 35S-cysteine was first given to rats followed by a tryptophan-fortified diet. Ingestion of the ‘tryptophan’ diet induced decrease of accumulated glutathione and increase of 35S-label in hepatic and serum proteins, especially that in serum albumin. 4) The most plausible explanation for these results is as follows: There are at least two pools of glutathione, differing from each other in their half-lives. The cysteine moiety of the ‘liver glutathione with shorter half-life’ is mobilized for protein synthesis when the other conditions are fulfilled and the amount of cysteine becomes rate-limiting. Otherwise, ‘cysteine’ continues to be stored in liver glutathione. Another pool of glutathione must serve for many reactions requiring sulfhydryl compounds in the liver.