Protective effect of (4R)-hexahydro-7,7-dimethyl-6-oxo-1,2,5-dithiazocine-4-carboxylic acid (SA3443), a novel cyclic disulfide, on immunologically induced liver injuries in mice.
The effects of (4R)-hexahydro-7,7-dimethyl-6-oxo-1,2,5-dithiazocine-4- carboxylic acid (SA3443), a novel cyclic disulfide, on new immunological liver injury models were investigated. The first liver injury model included a single injection of rabbit anti-basic liver protein antibody into DBA/2 mice. Serum transaminase activities showed a dose-dependent increase 42 hr after the antibody treatment. SA3443 significantly inhibited the elevation of serum transaminase activity and the histopathological changes of the liver in antibody-treated mice at doses of 100 to 300 mg/kg, p.o. The second hepatic failure model was based on an injection of lipopolysaccharide into BALB/c mice which had been previously treated with heat-killed Propionibacterium acnes (P. acnes). SA3443 reduced the lethal acute hepatic failure at doses of 100 to 300 mg/kg. Moreover, a distinct increase in lymphocyte-activating factor activity was detected in the supernatant of the culture medium of the liver macrophage/Kupffer cells isolated from the rat treated with P. acnes. SA3443, at 10(-6) to 10(-4) M, suppressed the release of the lymphocyte-activating factor activity from liver macrophage/Kupffer cells. These results suggest that SA3443 provides considerable protection against immunological liver injuries, and that the efficacy of SA3443 might be partially related to an inhibition of the increase in lymphocyte-activating factor activity.
Nakata
K
K
Central Research Laboratories, Santen Pharmaceutical Co., Ltd., Osaka, Japan.
Sasano
M
M
Matsunaga
K
K
Tanaka
M
M
Mita
S
S
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001392:Azocines / Q000494:pharmacology*; D004220:Disulfides / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology; D007728:Kupffer Cells / Q000276:immunology; D008074:Lipoproteins / Q000276:immunology; D008099:Liver / Q000276:immunology; D008107:Liver Diseases / Q000276:immunology / Q000517:prevention & control*; D008264:Macrophages / Q000276:immunology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D011425:Propionibacterium acnes / Q000276:immunology; D011506:Proteins / Q000276:immunology; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains
D001392:Azocines; D004220:Disulfides; D007375:Interleukin-1; D008074:Lipoproteins; D008565:Membrane Proteins; D011506:Proteins; C069788:SA 3443; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase