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Various medical surveys reveal that exceptionally high incidence rates of hepatic diseases like hepatitis and cirrhosis have occurred to Korean peoples, and even the viral hepatitis has been considered to be an endemic disease in this country. Therefore, we have made efforts to search for liver-protective/therapeutic agents from medicinal plants during the past 5 years. As a first step, we made literature survey in which 59 plants were described to be useful for the treatments of various hepatic diseases, even though their exact pathological nature had not been characterized. Among 59 plants, 44 plants were collected in Korea and their alcoholic extracts were prepared. Then the extracts were subject to screening of their potential liver-protective activities against liver damage induced by CCl4 in mice. The primary screening data indicated that six plants, Alisma orientate (Alismataceae), Atractylodes japonica (Compositae), Cyperus rotudus (Cyperaceae), Gentiana scrabra (Gentianaceae), Plantago asiatica (Plantaginaceae), and Polygonatum japonicum (Liliaceae) showed significant liver-protective activities to CCl4 intoxication in mice. Then we selected one plant for further studies, which was Plantago asiatica semen because it grows abundantly. Subsequent work was the isolation of active principle from Plantago asiatica semen. An iridoid glucoside, namely aucubin was isolated, as a candidate for the active principle. Then this compound was evaluated its liver-protective activities against liver damages induced by three different toxic substances; CCl4, alpha-amanitin and D-galactosamine. We found that aucubin exhibited potent protection from liver damages produced by CCl4 and alpha-amanitin, but not by D-galactosamine intoxication. In the meantime, we met a difficulty, that was, the aucubin content in Plantago asiatica semen. was very low. So we began to seek another plant as a source of aucubin. Aucuba japonica (Cornaceae) was selected for this purpose because it was reported that this plant had relatively high amount of aucubin. Soon its alcoholic extract was prepared and potential liver-protective activities were again investigated by using rat intoxicated with CCl4. The extract showed marked liver-protective activities: protections from decreasing biliary excretion caused by CCl4 intoxication, from increasing serum transaminases activities. In addition, histological findings of liver biopsy samples also supported the protective activities of the exract. Accordingly we isolated more aucubin from fresh leaves of Aucuba japonica to carry out further studies on liver-protective activities of this iridoid glucoside, (yield was 1g from 2kg of fresh leaves). The results obtained from successive experiments were the followings: aucubin showed marked protection from both CCl4 and alpha-amanitin poisonings; aucubin itself exhibited some degree of inhibitory effects on liver RNA and protein biosynthesis, however it was not potent; such inhibitory effect may account for a possible mechanism of liver-protective activities; aucubin counteracted severe depression of liver RNA synthesis caused by alpha-amanitin. Pretreatment of aucubin (60mg/kg) 30 min before alpha-amanitin administration prevented severe hypoglycemia produced by alpha-amanitin intoxication. Aucubin may be used for a good antidote for fatal mushroom poisoning caused by Amanita phalloides; it should be also noted that more than 50% complete recovery was achieved, even when the administration of aucubin (100mg/kg, i.p.) was withheld for 12 hrs after alpha-amanitin challenge. All the results indicated that aucubin appeared to be a potential in liver-protective agent and at least an antidote for Amanita mushroom poisoning. Thus we studied acute toxicity of aucubin itself. Results obtained from toxicity study indicated that the minimum lethal dose of aucubin appeared to be more than g unit, because a does of 900mg/kg, i.p. did not cause any death in mice. Also multiple doses (day 1, 3, 5 and 7; 20-80mg/kg, i.p) did not cause any alteration in blood serum enzymes activities, and no significant histological changes were observed by these doses. Consequently aucubin seemed to be low toxic substance.
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