Studies on hepatoprotective drugs. Part 12. Hepatoprotective and Hepatotoxic Activities of Sophoradiol Analogs on Rat Primary Liver Cell Cultures.

Abstract

As a part of our studies of hepatoprotective drugs, we prepared kaikasaponin I (2), sophoradiol monoglucuronide (SoMG, 3) and sophoradiol (4) from kaikasaponin III (1). We examined the hepatoprotective effects of these analogs, using immunologically-induced liver injury in primary cultured rat hepatocytes and found that compound 1 was more effective than soyasaponin I (1a) while 2 was more effective than 1. On the other hand, 3 was less effective than 2 at 30-200 microm. Further, compound 3 was strongly cytotoxic at 500 microM while 4 exhibited hepatoprotective activity at the same dose, although less potent. When the cytotoxicity toward hepatocytes of these analogs was tested, only 3 was cytotoxic at doses of 200 and 500 microM. This is the first example of an oleanene glucuronide (OG) which is cytotoxic toward hepatocytes. Compound 3 exhibited hepatoprotective activity at 200 microM, while it was also cytotoxic at the same dose without antiserum. Therefore, the hepatoprotective activity of OG represents a balance between a hepatoprotective action and its cytotoxicity toward hepatocytes.

Hepatoprotective Constituents in Plants 14. Effects of Soyasapogenol B, Sophoradiol, and Their Glucuronides on the Cytotoxicity of tert-Butyl Hydroperoxide to HepG2 Cells1)

“…Next, we examined the hepatoprotective activity of several glucuronides which showed potent protective activity to in vitro immunological injury of rat primary hepatocyte cultures, 1,19) together with their aglycones, soyasapogenol B (1d) and sophoradiol (2d). The glucuronides investigated were soyasaponins I (1a), III (1b), soyasapogenol B monoglucuronide (SBMG, 1c), kaikasaponins III (2a), I (2b), and sophoradiol monoglucuronide (SoMG, 2c).…”

“…1,22) Materials Soyasapogenol B and sophoradiol and their glucuronides have been isolated from some fabaceous plants according to previous papers. 1,19) The effects of soyasapogenol B, sophoradiol, their glucuronides, and glycyrrhizin on the hepatotoxicity of tert-butyl hydroperoxide (t-BuOOH) in a human-liver-derived cell line (HepG2 cells) were investigated. Glycyrrhizin showed significant dose-dependent protective effects against the cytotoxicity of t-BuOOH.…”

“…16) In a series of studies of hepatoprotective drugs, we devised an in vitro assay method in which the extent of immunological liver injury was measured in rat primary hepatocytes cultures. 17) We examined the preventive effect of soyasapogenol B 18,19) and sophoradiol 1) glucuronides using this method, and elucidated some structure-activity relationships.…”

Hepatoprotective Activity of the Constituents in Swertia pseudochinensis

“…Then, the cells were incubated at 37°C in a humidified 5% CO 2 and 95% air atmosphere. After 3 h incubation, the culture medium was changed and cells were incubated continuously for another 24 h. [9][10][11][12] Hepatocyte Injury by CCl 4 In order to decide suitable CCl 4 concentration for GOT measure, 20 ml CCl 4 /DMSO solution (50 mM) and 5, 7.5, 10, 15, 20 ml CCl 4 /DMSO solution (500 mM) were respectively added, into 1 ml of the culture medium for liver cells preincubated for 1 d. After incubating for 1 h, each GOT value was measured. Analyzing the results of GOT measure, we finally selected 500 mM CCl 4 /DMSO solution 7.5 ml (final concentration of CCl 4 was 3.75 mM) to use in the following hepatocyte injury experiment.…”

“…By various column chromatography of the methanolic extract prepared from the dried whole plant of the crude drug, we have obtained 5 iridoids compounds as swertiamarin (1), sweroside (2), gentiopicroside (3), amarogentin (8), amaroswerin (9) and 8 xanthones compounds, a new compound (5), which was named pseudonolin, together with the following known compounds, tetrahydroswertianolin (4), bellidifoline (6), swertianolin (7), metylswertianin (10), 1-hydroxy-3,7-dimethoxyxanthone (11), methylbellidiforlin (12), desmethylbellidifolin (13). [1][2][3][4] Among them, 5 was a new compound and 11 was isolated for the first time from Swertia genus.…”