concanavalin-a and osthol

Prevention of hepatitis is a worldwide issue. For most patients with liver disease, hepatoprotective drugs are required. But there are only a few hepatoprotective drugs available. Osthole is a coumarin compound and protects the liver from hepatitis by preventing the development of apoptosis. However, osthole exhibits low water solubility, and some structural modifications are required for sufficient hepatoprotection upon oral administration. We synthesized 28 osthole derivatives, and then studied their effects by using mice concanavalin A (Con A) -induced hepatitis. The osthole derivatives No.1, 9 and 19 showed stronger inhibition of Con A-induced elevation of plasma alanine aminotransferase (ALT). Oral administration of osthole at the dose of 100 mg/kg (n=10) inhibited 38.0% of the Con A-induced elevation of plasma ALT. In contrast, oral administration of Nos. 1, 9 and 19 at the dose of 100 mg/kg (n=5) caused 68.7%, 62.5% and 88.3% inhibition of the Con A-induced elevation of plasma ALT, respectively. These synthetic osthole derivatives could contribute to the development of hepatoprotective drugs effective for various types of liver diseases on oral administration.

Topics: Alanine Transaminase; Animals; Apoptosis; Chemical and Drug Induced Liver Injury; Concanavalin A; Coumarins; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Indicators and Reagents; Mice; Mice, Inbred BALB C; T-Lymphocytes

The effects of coumarin derivatives, osthole, imperatorin, Pd-Ia, Pd-II and Pd-III, on mice concanavalin A (Con A) (0.2 mg/mouse, i.v.)-induced hepatitis were studied. At the dose of 200 mg/kg (i.p.), these coumarins inhibited more than 90% of the Con A-induced elevation of plasma alanine aminotransferase activity, but glycyrrhizin (200 mg/kg, i.p.) caused only 45% inhibition. At the dose of 100 mg/kg (i.p.), osthole produced the strongest inhibition among these coumarins. The inhibitory activity of osthole is lost when its 7-methoxy group is replaced by a 7-hydroxy group to form osthenol. The present results showed that coumarin derivatives inhibited Con A-induced hepatitis, with osthole being the most inhibitory.

Topics: Alanine Transaminase; Animals; Anticoagulants; Concanavalin A; Coumarins; Female; Furocoumarins; Glycyrrhizic Acid; Hepatitis, Animal; Liver; Mice; Mice, Inbred BALB C