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.