Glutathione deficiency leads to mitochondrial damage in brain.
Glutathione deficiency induced in newborn rats by giving buthionine sulfoximine, a selective inhibitor of gamma-glutamylcysteine synthetase, led to markedly decreased cerebral cortex glutathione levels and striking enlargement and degeneration of the mitochondria. These effects were prevented by giving glutathione monoethyl ester, which relieved the glutathione deficiency, but such effects were not prevented by giving glutathione, indicating that glutathione is not appreciably taken up by the cerebral cortex. Some of the oxygen used by mitochondria is known to be converted to hydrogen peroxide. We suggest that in glutathione deficiency, hydrogen peroxide accumulates and damages mitochondria. Glutathione, thus, has an essential function in mitochondria under normal physiological conditions. Observations on turnover and utilization of brain glutathione in newborn, preweaning, and adult rats show that (i) some glutathione turns over rapidly (t 1/2, approximately 30 min in adults, approximately 8 min in newborns), (ii) several pools of glutathione probably exist, and (iii) brain utilizes plasma glutathione, probably by gamma-glutamyl transpeptidase-initiated pathways that account for some, but not all, of the turnover; thus, there is recovery or transport of cysteine moieties. These studies provide an animal model for the human diseases involving glutathione deficiency and are relevant to oxidative phenomena that occur in the newborn.
Jain
A
A
Department of Pediatrics, Cornell University Medical College, New York, NY 10021.
Mårtensson
J
J
Stole
E
E
Auld
P A
PA
Meister
A
A
D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000254:growth & development / Q000473:pathology* / Q000648:ultrastructure; D019328:Buthionine Sulfoximine; D005260:Female; D005978:Glutathione / Q000031:analogs & derivatives / Q000097:blood / Q000172:deficiency*; D019803:Glutathione Disulfide; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure*; D008933:Mitochondrial Swelling; D051381:Rats; D011919:Rats, Inbred Strains
D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005978:Glutathione; D019803:Glutathione Disulfide