A new amphiphilic derivative, N-{[4-(lactobionamido)methyl]benzylidene}-1,1-dimethyl-2-(octylsulfanyl)ethylamine N-oxide, has a protective effect against copper-induced fulminant hepatitis in Long-Evans Cinnamon rats at an extremely low concentration compared with its original form alpha-phenyl-N-(tert-butyl) nitrone.
An amphiphilic alpha-phenyl-N-(tert-butyl) nitrone (PBN) derivative, N-{[4-(lactobionamido)methyl]benzylidene}-1,1-dimethyl-2-(octylsulfanyl)ethylamine N-oxide (LPBNSH), newly synthesized from its original form PBN in hopes of clinical use, was intraperitoneally administered to Long-Evans Cinnamon (LEC) rats every 2 days at the concentrations of 0.1, 0.5, 1.0, and 2.0 mg/kg. We found that LPBNSH protected against copper-induced hepatitis with jaundice in LEC rats at concentrations of 0.1 and 0.5 mg/kg, which were extremely low compared with that of PBN. It also effectively prevented the loss of body weight, reduced the death rate, and suppressed the increase in serum aspartate aminotransferase and alanine aminotransferase values arising from fulminant hepatitis with jaundice at the same concentrations. Similar results were observed when PBN was administered at the concentration of 150 mg/kg. Immunohistochemical analysis of 8-hydroxy-2'-deoxyguanosine and measurement of thiobarbituric acid-reactive substances in the liver showed that LPBNSH largely suppressed the formation of these oxidative products at same concentrations. No difference in the abnormal accumulation of copper in the liver between the LPBNSH administered and control groups was observed. From these results, it was concluded that LPBNSH exhibited liver-protective effects against fulminant hepatitis with jaundice at ca. 1/1000, 500 the molar concentration of PBN and, therefore, was clinically promising.
Asanuma
Taketoshi
T
Laboratory of Radiation Biology, Graduate School of Veterinary Medicine, Hokkaido University, Kita 18 Nishi 9, Kita-ku, Sapporo 060-0818, Japan. asanuma@vetmed.hokudai.ac.jp
Yasui
Hironobu
H
Inanami
Osamu
O
Waki
Kenji
K
Takahashi
Momoko
M
Iizuka
Daisuke
D
Uemura
Taketo
T
Durand
Grégory
G
Polidori
Ange
A
Kon
Yasuhiro
Y
Pucci
Bernard
B
Kuwabara
Mikinori
M
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology / Q000517:prevention & control*; D003300:Copper / Q000032:analysis / Q000633:toxicity*; D003497:Cyclic N-Oxides / Q000627:therapeutic use; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis; D004187:Disaccharides / Q000627:therapeutic use*; D007097:Imines / Q000627:therapeutic use*; D007150:Immunohistochemistry; D008099:Liver / Q000737:chemistry / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051381:Rats; D020332:Rats, Inbred LEC; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis
D000975:Antioxidants; D003497:Cyclic N-Oxides; D004187:Disaccharides; D007097:Imines; C524289:N-((4-(lactobionamido)methyl)benzylidene)-1,1-dimethyl-2-(octylsulfanyl)ethylamine N-oxide; D017392:Thiobarbituric Acid Reactive Substances; C029217:phenyl-N-tert-butylnitrone; D003300:Copper; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine