Osthole prevents anti-Fas antibody-induced hepatitis in mice by affecting the caspase-3-mediated apoptotic pathway.
Fas (Apo-1/CD95) ligand, which is a type II membrane protein, is a major inducer of apoptosis. Osthole is a coumarin derivative present in medicinal plants. The effect of osthole on hepatitis induced by anti-Fas antibody in mice was studied. Pretreatment of mice with osthole (10, 50, and 100 mg/kg, i.p.) prevented the elevation of plasma alanine aminotransferase (ALT) caused by anti-Fas antibody (175 microg/kg, i.v.). Administration of osthole to mice even at a dose of 10 mg/kg significantly inhibited of anti-Fas antibody-induced elevation of plasma ALT. Capase-3 is a cysteine protease, and treatment of mice with anti-Fas antibody caused an elevation of caspase-3 activity at 3.5 and 6 hr. Pretreatment of mice with osthole (100 mg/kg, i.p.) inhibited the elevation of caspase-3 activity caused by anti-Fas antibody. However, the addition of osthole (up to 10(-4)M) to a liver cytosol fraction isolated from mice treated with anti-Fas antibody did not inhibit caspase-3 activity in vitro. Thus, treatment of mice with osthole inhibited caspase-3 activity by an effect upstream of caspase-3 activation. The livers of mice treated with anti-Fas antibody contained apoptotic and dead cells; osthole attenuated the development of this apoptosis and cell death. The present results show that osthole prevented anti-Fas antibody-induced hepatitis by inhibiting the Fas-mediated apoptotic pathway.
Okamoto
Toshihiro
T
Research Laboratories, Nippon Chemiphar Co., Ltd., 1-22 Hikokawato, Misato, Saitama 341-0005, Japan.
Kawasaki
Toru
T
Hino
Okio
O
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000906:Antibodies / Q000009:adverse effects; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D003374:Coumarins / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D019014:fas Receptor / Q000276:immunology*
D000906:Antibodies; D003374:Coumarins; D019014:fas Receptor; D000410:Alanine Transaminase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; C046627:osthol