A novel biologically active seleno-organic compound--VI. Protection by ebselen (PZ 51) against galactosamine/endotoxin-induced hepatitis in mice.
Male albino NMRI mice were given 700 mg/kg galactosamine and 33 micrograms/kg salmonella endotoxin intraperitoneally. After 9 hr, serum sorbitol dehydrogenase activity had risen from 60 to 7320 U/l, SGOT from 90 to 5580, and SGPT from 70 to 10,440. When a similar dose of galactosamine alone or endotoxin alone was given, no significant liver injury was found. Animals pre-treated with an oral dose of ebselen (600 mg/kg 1-3 hr before galactosamine/endotoxin administration) were fully protected against this type of hepatitis. When pretreated 1 hr before intoxication with different doses of ebselen, significant dose-dependent reduction of serum enzyme activities was observed at doses higher than 1 mg/kg. After pre-treatment with 6 mg/kg ebselen, no biochemical or histological signs of liver lesions were detectable 36 hr after intoxication. In order to comparatively evaluate the model used, several established anti-inflammatory drugs were administered at doses which showed 50% effectiveness in preventing carageenan paw edema. A dose of 200 micrograms/kg dexamethasone, or 9 mg/kg indomethacin abolished galactosamine/endotoxin-induced enzyme release in our animals, as did the lipoxygenase pathway inhibitor diethylcarbamazine (78 mg/kg). In contrast, administration of cyclooxygenase pathway inhibitors such as aspirin (220 mg/kg) or ibuprofen (45 mg/kg) failed to prevent hepatitis. The effect of ebselen was also investigated in four different models of acute drug-induced liver damage. A dose of 600 mg/kg of the organic selenium compound was ineffective or weakly active in benzo(alpha)pyrene- or phenobarbital-treated mice which were intoxicated by intraperitoneal administration of 350 or 400 mg/kg body weight of paracetamol. Similarly negative results were obtained against bromobenzene-induced hepatotoxicity (520 mg/kg bromobenzene i.p.), carbon tetrachloride intoxication (3.2 g/kg), or allyl alcohol-induced liver damage (60 mg/kg). The selective efficacy of ebselen against galactosamine/endotoxin induced liver damage is interpreted in terms of its recently recognized ability to inhibit the formation of leukotrienes.
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001393:Azoles / Q000627:therapeutic use*; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control*; D003907:Dexamethasone / Q000494:pharmacology; D004049:Diethylcarbamazine / Q000494:pharmacology; D004731:Endotoxins; D005688:Galactosamine; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D019803:Glutathione Disulfide; D006520:Hepatitis, Animal / Q000139:chemically induced*; D007052:Ibuprofen / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D054833:Isoindoles; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D008297:Male; D051379:Mice; D016566:Organoselenium Compounds; D012643:Selenium / Q000627:therapeutic use*; D013997:Time Factors
D001393:Azoles; D004731:Endotoxins; D054833:Isoindoles; D016566:Organoselenium Compounds; C042986:ebselen; D005688:Galactosamine; D003907:Dexamethasone; D007064:L-Iditol 2-Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione; D012643:Selenium; D019803:Glutathione Disulfide; D004049:Diethylcarbamazine; D007052:Ibuprofen; D007213:Indomethacin