The glutathione precursor L-2-oxothiazolidine-4-carboxylic acid protects against liver injury due to chronic enteral ethanol exposure in the rat.
L-2-oxothiazolidine-4-carboxylic acid (OTC) is a cysteine prodrug that maintains glutathione in tissues. Here, its effect on alcohol-induced liver injury in an enteral alcohol feeding model was investigated. Male Wistar rats were given control high-fat or ethanol containing diets enterally for 4 weeks. Treated rats received 500 mg/kg/d of dietary OTC. Ethanol delivery, weight gain, and the cyclic pattern of ethanol in the urine were not different between the OTC-ethanol and ethanol groups. After 4 weeks, serum aspartate transaminase (AST), necrosis and inflammation were elevated significantly by ethanol compared with appropriate high-fat controls, effects blocked by OTC. Moreover, ethanol elevated hepatic tumor necrosis factor alpha (TNF-alpha) messenger RNA (mRNA) and the nuclear transcription factor nuclear factor kappaB (NFkappaB) 2-3 fold. NFkappaB in isolated Kupffer cells was also increased by ethanol. These effects were all blocked by OTC treatment. Additionally, superoxide production was higher in Kupffer cells isolated from ethanol-treated rats, an effect blunted by OTC. OTC also increased circulating glutathione (GSH) levels about 2-fold; however, GSH levels were not affected by ethanol or OTC in livers from the groups studied. Surprisingly, GSH was elevated by ethanol and OTC treatment in isolated Kupffer cells about 2-fold. Moreover, GSH (Ki-10 micromol/L) and cysteinyl-glycine, but not oxidized glutathione (GSSG) or OTC, blunted the LPS-induced increase in calcium in isolated Kupffer cells, possibly by activating a glycine-gated chloride channel due to their structural similarity with glycine. Collectively, it is concluded that GSH is protective, in part, by increasing circulating GSH, which blunts activation of Kupffer cells via the glycine-gated chloride channel.
Iimuro
Y
Y
Laboratory of Hepatobiology, Department of Pharmacology, Chapel Hill, NC, USA.
Bradford
B U
BU
Yamashina
S
S
Rusyn
I
I
Nakagami
M
M
Enomoto
N
N
Kono
H
H
Frey
W
W
Forman
D
D
Brenner
D
D
Thurman
R G
RG
D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology / Q000517:prevention & control; D000431:Ethanol / Q000008:administration & dosage* / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D007441:Intubation, Gastrointestinal; D007728:Kupffer Cells / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008107:Liver Diseases / Q000517:prevention & control*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D011355:Prodrugs / Q000494:pharmacology; D011761:Pyrrolidonecarboxylic Acid; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000494:pharmacology*; D053778:Thiazolidines; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D016328:NF-kappa B; D011355:Prodrugs; D012333:RNA, Messenger; D013844:Thiazoles; D053778:Thiazolidines; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D001219:Aspartate Aminotransferases; D005978:Glutathione; D011761:Pyrrolidonecarboxylic Acid; C029536:2-oxothiazolidine-4-carboxylic acid