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 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.
Watanabe
Toshiyuki
T
Medicinal Safety, Research Laboratories, Sankyo, Co., Ltd., 717 Horikoshi, Fukuroi, Shizuoka 437-0065, Japan.
Sagisaka
Hideki
H
Arakawa
Shingo
S
Shibaya
Yukari
Y
Watanabe
Mayumi
M
Igarashi
Isao
I
Tanaka
Kohji
K
Totsuka
Shigeo
S
Takasaki
Wataru
W
Manabe
Sunao
S
D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity; D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D019328:Buthionine Sulfoximine / Q000008:administration & dosage / Q000633:toxicity*; D003404:Creatinine / Q000097:blood; D004357:Drug Synergism; D005978:Glutathione / Q000032:analysis / Q000172:deficiency*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D023421:Models, Animal; D009929:Organ Size / Q000187:drug effects; D018675:Toxicity Tests; D014867:Water / Q000008:administration & dosage
D014867:Water; D000082:Acetaminophen; D019328:Buthionine Sulfoximine; D003404:Creatinine; D000410:Alanine Transaminase; D005978:Glutathione