Liver, Pancreas, and Biliary TractGenipin, a metabolite derived from the herbal medicine Inchin-ko-to, and suppression of Fas-induced lethal liver apoptosis in mice☆
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Drugs, antibodies, and chemicals
Extract powders of ICKT and the Kampo medicine Sho-saiko-to were obtained from Tsumura & Co. (Tokyo, Japan). Glycyrrhizin (GLN) was purchased as Stronger Neo-Minophagen C from Minophagen Pharmaceutical Co. (Tokyo, Japan). Ursodeoxycholic acid was from Tokyo Tanabe Pharmaceutical Co. (Tokyo, Japan). A monoclonal anti-murine Fas antibody Jo2 and fluorescein isothiocyanate (FITC)-labeled Jo2 were obtained from Pharmingen (San Diego, CA). Other chemicals were purchased from Sigma Chemical Co. (St.
Protection from Fas-mediated death by ICKT
When 6.7 μg of the anti-Fas antibody Jo2 was injected IV in 4–5-week-old female BALB/c mice, severe hepatic failure rapidly developed and all control mice died within 24 hours. Two Kampo (Chinese/Japanese herbal) medicines, ICKT and Sho-saiko-to, and GLN and ursodeoxycholic acid, approved drugs for the treatment of liver diseases, were administered for 4 days before Jo2 injection. Fifteen of the 20 mice treated with 2 g/kg ICKT survived the antibody administration (Figure 1; P < 0.0001) and
Discussion
In this study we used a fulminant hepatitis model, first reported by Ogasawara et al.,3 that is based on massive liver cell apoptosis caused by IP or IV injection of the agonistic anti-Fas antibody Jo2. Using the same model, several researchers have examined the effects of apoptosis-modulating agents on Fas-mediated lethal liver injury. Mice overexpressing bcl-2, a gene with antiapoptotic properties, specifically in the liver, were protected from the lethality of Jo2 antibody treatment.27
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Address requests for reprints to: Masahiro Yamamoto, Ph.D., Kampo Pharmacology Department, Tsumura Central Research Laboratories, Tsumura & Co., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-1192, Japan. e-mail: [email protected]; fax: (81) 298-89-3867.