Intrahepatic delivery of glutathione by conjugation to dextran.
Glutathione was covalently attached to dextran (T-40) by the CNBr activation method. The compound obtained was a water-soluble powder containing 10 (w/w%) glutathione, which was gradually released from the conjugate in aqueous media. Mice depleted of glutathione by treatment with buthionine sulfoximine, a potent inhibitor of gamma-glutamylcysteine synthetase, exhibited a significant increase in hepatic glutathione level after intravenous injection of the conjugate. In mice given a lethal dose of acetaminophen, the survival rate increased progressively with coadministration of the conjugate, whereas little improvement was found when free glutathione was given. The conjugate maintained the serum transaminase activities at lower level after acetaminophen administration. These findings suggest that the dextran conjugate of glutathione is transported into hepatic cells and is intracellularly hydrolyzed to free form, which protects mice from hepatotoxicity due to acetaminophen.
Kaneo
Y
Y
Department of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Hiroshima, Japan.
Fujihara
Y
Y
Tanaka
T
T
Kozawa
Y
Y
Mori
H
H
Iguchi
S
S
D000082:Acetaminophen / Q000037:antagonists & inhibitors; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D003911:Dextrans / Q000378:metabolism; D005470:Fluorometry; D005978:Glutathione / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D019803:Glutathione Disulfide; D008099:Liver / Q000378:metabolism*; D008107:Liver Diseases / Q000517:prevention & control; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics*
D003911:Dextrans; D011355:Prodrugs; D000082:Acetaminophen; D005978:Glutathione; D019803:Glutathione Disulfide