Effect of inhibition of gamma-glutamyltranspeptidase by AT-125 (acivicin) on glutathione and cysteine levels in rat brain and plasma.
AT-125 (Acivicin) is an inhibitor of gamma-glutamyltranspeptidase (gamma-GTP) which initiates glutathione catabolism to cysteine. We measured plasma and brain glutathione and cysteine in rats treated with AT-125. Six h after AT-125 treatment, plasma glutathione had increased 6-fold and plasma cysteine had fallen significantly. Brain cysteine fell after 24 h of AT-125 treatment, and brain glutathione had also decreased 18%. AT-125 pretreatment inhibited brain uptake of 35S when it was given as 35S-GSH but had no effect when it was given as 35S-cysteine. These results suggest that plasma glutathione is catabolized by gamma-GTP, and cysteine derived from it is taken up by the brain. N-acetylcysteine was administered to AT-125 treated rats in an attempt to supply cysteine to the brain in the face of gamma-GTP inhibition. N-acetylcysteine supported brain glutathione levels, suggesting that it can serve as a source of cysteine under these conditions.
Hill
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Von Hoff
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Burk
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D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism*; D003545:Cysteine / Q000097:blood / Q000378:metabolism*; D005978:Glutathione / Q000097:blood / Q000378:metabolism*; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D010080:Oxazoles / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors*
D000903:Antibiotics, Antineoplastic; D007555:Isoxazoles; D010080:Oxazoles; D005723:gamma-Glutamyltransferase; D005978:Glutathione; D003545:Cysteine; C006303:acivicin