Glutathione deficiency decreases tissue ascorbate levels in newborn rats: ascorbate spares glutathione and protects.
Glutathione deficiency in newborn rats, produced by administration of L-buthionine-(S,R)-sulfoximine, a transition-state inactivator of gamma-glutamylcysteine synthetase, decreases ascorbate levels of kidney, liver, brain, and lung. These tissues, especially their mitochondria, undergo severe damage and the animals die within a few days. When glutathione levels are markedly decreased, ascorbate levels decrease leading to formation of dehydroascorbate, which is degraded. Ascorbate has high antioxidant activity, but it (and other antioxidants such as alpha-tocopherol) must be maintained in reduced forms. These studies show in vivo that an important function of glutathione is to maintain tissue ascorbate. Administration of large doses of ascorbate (but not of dehydroascorbate) to buthionine sulfoximine-treated newborn rats decreases mortality, leads to normal levels of ascorbate, and spares glutathione. Newborn rats given lower doses of buthionine sulfoximine develop cataracts that, as shown previously, can be prevented by giving glutathione monoester; as found here, such cataracts can be partially prevented by administration of high doses of ascorbate or dehydroascorbate. Ascorbate spares glutathione indicating that these compounds have similar antioxidant actions. Ascorbate may have reductive functions that are not efficiently performed by glutathione. Although glutathione normally functions to maintain ascorbate, alpha-tocopherol, and other cellular components in reduced states, ascorbate can serve as an essential antioxidant in the presence of severe glutathione deficiency.
Mãrtensson
J
J
Department of Biochemistry, Cornell University Medical College, New York, NY 10021.
Meister
A
A
Mrtensson
J
J
D000818:Animals; D000831:Animals, Newborn; D001205:Ascorbic Acid / Q000378:metabolism* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019328:Buthionine Sulfoximine; D005260:Female; D005978:Glutathione / Q000172:deficiency* / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D009928:Organ Specificity; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values
D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005978:Glutathione; D001205:Ascorbic Acid