A protective effect of glutathione-dextran macromolecular conjugates on acetaminophen-induced hepatotoxicity dependent on molecular size.
Glutathion (GSH) was covalently attached to dextrans with various molecular weights of 2, 5, 10, 40, and 70 kDa by the cyanogen bromide activation method. The conjugates obtained synthetically were white or pale yellowish powders containing 6-10% (w/w) of GSH. The average molecular weights of the conjugates were estimated to be larger and the molecular weight distribution was a little broader than that of each original dextran. The conjugates significantly stabilized GSH and liberated it gradually under physiological conditions (t1/2 = 0.99-1.6h). Mice depleted of GSH by treatment with buthionine sulfoximine, a potent inhibitor of gamma-glutamylcysteine synthetase, exhibited a significant increase in hepatic GSH level after intravenous injection of the conjugates. In mice given a hepatotoxic dose of acetaminophen, the survival rate increased progressively with coadministration of the conjugates, whereas a small improvement was found when free GSH was given. The conjugate of GSH attached to dextran with the molecular weight of 40 kDa exhibited the highest prophylactic effect on acetaminophen-induced hepatotoxicity in mice. The prolonged retention of the conjugates of larger molecular weight in the circulation would cause a higher hepatic accumulation. These results suggested that molecular size would be the most critical factor in the delivery of GSH, as a dextran conjugate, into the liver.
Kaneo
Y
Y
Department of Biopharmaceutics, School of Pharmacy, Fukuyama University, Hiroshima, Japan.
Ogawa
K
K
Tanaka
T
T
Fujihara
Y
Y
Iguchi
S
S
D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D000963:Antimetabolites / Q000633:toxicity; D001219:Aspartate Aminotransferases / Q000378:metabolism; D019328:Buthionine Sulfoximine; D056486:Chemical and Drug Induced Liver Injury; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D003488:Cyanogen Bromide / Q000737:chemistry; D003692:Delayed-Action Preparations; D003911:Dextrans / Q000737:chemistry / Q000378:metabolism*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D005978:Glutathione / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008107:Liver Diseases / Q000517:prevention & control; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000633:toxicity; D051379:Mice; D008970:Molecular Weight; D015996:Survival Rate
D000963:Antimetabolites; D003692:Delayed-Action Preparations; D003911:Dextrans; D008717:Methionine Sulfoximine; D000082:Acetaminophen; D019328:Buthionine Sulfoximine; D001219:Aspartate Aminotransferases; D005978:Glutathione; D003488:Cyanogen Bromide