A NOVEL MODEL OF CONTINUOUS DEPLETION OF GLUTATHIONE IN MICE TREATED WITH L-BUTHIONINE (S,R)-SULFOXIMINE

L-Buthionine (S,R)-sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, was administered to mice via drinking water for 14 days in order to establish an animal model with continuously depleted levels of GSH. No toxicity was observed at 20 mM BSO, even though a significant decrease in live...

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Published in:	Journal of toxicological sciences Vol. 28; no. 5; pp. 455 - 469
Main Authors:	WATANABE, Toshiyuki, SAGISAKA, Hideki, ARAKAWA, Shingo, SHIBAYA, Yukari, WATANABE, Mayumi, IGARASHI, Isao, TANAKA, Kohji, TOTSUKA, Shigeo, TAKASAKI, Wataru, MANABE, Sunao
Format:	Journal Article
Language:	English
Published:	Japan The Japanese Society of Toxicology 01-01-2003 Japan Science and Technology Agency
Subjects:	Acetaminophen Acetaminophen - metabolism Acetaminophen - toxicity Administration, Oral Alanine Transaminase - blood Animals Buthionine Sulfoximine - administration & dosage Buthionine Sulfoximine - toxicity Creatinine - blood Drug Synergism Glutathione - analysis Glutathione - deficiency Glutathione depletion Idiosyncrasy L-Buthionine (S,R)-sulfoximine Liver Liver - drug effects Liver - enzymology Liver - pathology Male Mice Mice, Inbred Strains Models, Animal Organ Size - drug effects Reactive intermediate Toxicity Tests Water - administration & dosage
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Summary:	L-Buthionine (S,R)-sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, was administered to mice via drinking water for 14 days in order to establish an animal model with continuously depleted levels of GSH. No toxicity was observed at 20 mM BSO, even though a significant decrease in liver weight was observed at 30 mM BSO. GSH levels in the liver, kidney, brain, lung, heart, spleen, pancreas, small intestine, large intestine, skeletal muscle, plasma and blood cells from mice given 20 mM of BSO were all less than those from the control mice continuously throughout a 24-hr period. The ratios of the GSH levels to that of the control were 46.4% and 16.7% in the liver and kidney, respectively, suggesting a decrease in GSH conjugation activity in vivo by GSH depletion. Liver cytochrome P450 content and UDP-glucuronosyltransferase activity to p-nitrophenol were not influenced by the BSO dosing. To confirm the adequacy of this GSH-depletion model, 0.125 or 0.25% of acetaminophen (APAP) was administered via diet to this model for 14 days. Nine out of the ten mice given both 20 mM BSO and 0.25% APAP died on Day 2, and remarkable necrosis was observed in the hepatocytes and renal tubular epithelium. Moreover, focal necrosis of hepatocytes with proliferation of fibroblasts was observed on Day 15 in some mice coadministered 20 mM BSO and 0.125% APAP. However, no toxicity was observed in mice given APAP alone. Based on these results, a mouse given 20 mM of BSO via drinking water for 14 days was concluded to be an animal model with continuously depleted levels of GSH in various organs without toxicity. This model shows high susceptibility to toxicity induced by chemicals which are metabolized to electrophilic and reactive metabolite(s), such as APAP.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0388-1350 1880-3989
DOI:	10.2131/jts.28.455