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Chemico-pharmacological studies on saponins of Panax ginseng C. A. Meyer. II. Pharmacological part.

The pharmacological properties of seven pure saponins isolated from Panax ginseng C. A. Meyer were studied. 1. The ginseng saponins showed weak toxicities in mice. Especially, Rg1, Rf and Rb 1, which contained glucose as a sugar component, were weaker in their toxicities than the rest, which contained arabinose and/or rhamnose. It was also noted that the saponins containing protopanaxadiol as sapogenin were more toxic than those containing protopanaxatriol. 2. All the saponins diminished ACh-induced contraction of the isolated ileum of the guinea pig. On the other hand high concentrations of Rb 2 caused contraction of the ileum by itself. 3. All of the saponins induced a decrease in heart rate and showed biphasic actions on the blood pressure in rats, while they little affected respiration. They caused blood pressure fall preceded by slight rise. Among them, Rg 1 showed the most prominent action and it produced a blood pressure rise with doses of 30 to 100 mg/kg. The pressor as well as depressor action was not influenced by the pretreatment with any of atropine, diphenhydramine, phentolamine and propranolol. 4. Rg 1 and Re showed vasodilator action in dogs, the potencies of which were 1/20 and 1/50 of that of papaverine, respectively. Rc and Rb 2 showed very weak vasodilator actions but Rb 1 did not. 5. Among the 7 saponins, Rd, Re and Rb 2 showed more potent hemolytic actions than those of the rest and the potencies were proportional to their toxicities. 6. Whereas single administration of Rf, Re and Rd significantly suppressed the conditioned avoidance response, repeated administration of them caused facilitation of the response. On the other hand, Rb 2 always showed very weak suppressant action. 7. Rg 1, Rf, Re and Rd significantly suppressed the fighting of mice induced by foot shock, while Rb 1, Rb 2 and Re little affected the fighting. 8. All the saponins showed antifatigue action. They markedly increased the movement after compulsory gait and the action was consistent and independent of their action on the movement before compulsory gait. 9. The saponins showed moderate depressant actions on the EEG and the behavior in cats. They were qualitatively similar in their actions, although Rg 1, Re and Rb 2 were more potent than the rest. They also suppressed EEG arousal response induced by electrical stimulation of the mid brain in cats.

Acetylcholine↗

[The structure of glyuranolide, a new triterpene of Glycyrrhiza uralensis Fisch].

Using a medium pressure liquid chromatographic system, a new triterpene lactone named glyuranolide [3 beta, 22 alpha-dihydroxy-11-oxo-delta 12-oleanene-27 alpha-methoxy carbonyl-29-oic acid (29, 22 alpha-) lactone.] was isolated from the crude sapogenins of Glycyrrhiza uralensis Fisch. Its structure was elucidated by IR, UV, FAB-MS, and various NMR spectra (including NOE, BBD, INEPT, SR, COSY, NOESY etc.).

Chemical Phenomena↗

An outbreak of suspected solanine poisoning in schoolboys: Examinations of criteria of solanine poisoning.

Seventy eight schoolboys became ill after eating potato at lunch on the second day of the autumn term. Seventeen of the boys required admission to hospital. The gastrointestinal, circulatory, neurological and dermatological findings and the results of laboratory investigations were in keeping with solanine poisoning. The illness affected the junior boys and all the monitors but no other senior boys or staff. This pattern was compatible with the consumption of a relatively small number of toxic potatoes believed to have come from a bag (A) left in the stores since the summer term. The amount of solanine in potato waste recovered after the meal was excessive as assessed by its anticholinesterase activity. The amount of alpha-solanine and alpha-chaconine in the flesh and peel of potatoes from a bag (B) known to have been left from the previous term was high. The anomalously narrow margin between the solanidine alkaloid content reported for normal and toxic potatoes might perhaps result from an excessive synthesis by the latter of additional, related steroids, such as sapogenins and saponins, which, by promoting gastrointestinal absorption or other means, might enhance the toxicity of solanidine alkaloid.

Adolescent↗

[Hypocholesterolemic effect of phytoecdysones during experimental hypercholesterolemia in rats].

The most active hypocholesterolemic preparation, affecting the absorption of 3H1-cholesterol in small intestine of rats with experimental hypercholesterolemia, proved to be I-hydroxyecdisterone; the activity was gradually decreased in the following series of preparations: ecdisterone, steroid sapogenine allyogenone, ciasterone and ecdisterone 25 acetate. Thus, the hypocholesterolemic activity of the preparations was increased with an increase in the content of hydroxy groups in the molecules. After daily administration of ecdisterone at a dose of 2.5 mg/kg into the animals with hypercholesterolemia within 3, 6 and 8 weeks, content of cholesterol in blood plasma was decreased by 7.0%, 16.9% and 29%, respectively; this phenomenon was accompanied by a decrease of the cholesterol content in erythrocyte membranes as well as in microfilaments of erythrocyte border by 26% and 34%, respectively. Amount of phospholipids and the ratio cholesterol/phospholipids were also normalized in the membranes studied. The data obtained suggest that competitive relationship occurs between cholesterol and the hypocholesterolemic drugs during binding with the membrane sites depending on their concentrations in blood plasma, intestine lumen and on the content in the membranes.

Animals↗

Photosensitivity in South Africa. VIII. Ovine metabolism of Tribulus terrestris saponins during experimentally induced geeldikkop.

Geeldikkop was induced in a sheep by dosing it orally with a crude extract of the steroidal saponins from Tribulus terrestris. GC-MS analysis of the sheep's ruminal contents, bile, faeces and urine for free and conjugated sapogenins, revealed the general features of the metabolic pathway by which diosgenin and yamogenin glycosides were converted into the glucuronides of epismilagenin and episarsasapogenin, the major constituents of the biliary crystals that usually form during geeldikkop. Other steroidal saponins in the T. terrestris extract, including those derived from tigogenin, neotigogenin, gitogenin and neogitogenin appear to be non-lithogenic. The implications of these findings are discussed.

Animals↗

Cytotoxicity of triterpenoid saponins. Part 1: Activities against tumor cells in vitro and hemolytical index.

Genuine saponins from Solidago virgaurea L., Heteropappus altaicus (Willd.) Novopokr., H. biennis (Ldb.) Tamamsch., and Helianthus annuus L. (Asteraceae) as well as related carbohydrate modified glycosides of polygalacic acid and echinocystic acid were investigated in view of their structure related cytotoxicity in the YAC-1- and in the P-815-tumor cell model. The cytotoxic activities are influenced by both, the O-glycosylation pattern at carbon atom 3 and 28 of the sapogenin. The IC50-values of bisdesmosides of polygalacic acid are lower than those of the corresponding prosapogenins. The acylglycosidic carbohydrate sequence 1-fucose-2 <-- 1-rhamnose-4 <-- 1-xylose-3 <-- 1-rhamnose of these bisdesmosides showed the highest cytotoxic effect. One etherglycosidic linked glucose unit at C-3 of the aglycone is essential, a difference in activity to the disaccharide laminaribiose at the same position cannot be observed. In the case of echinocystic acid glycosides the acylglycosidic carbohydrate sequence 1-arabinose-2 <-- 1-rhamnose-4 <-- 1-glucose seems to influence the rate of the cytotoxic effects. By comparing the concentration of the saponins with the complete hemolysis time it is possible to determine the hemolytical index in a very short time. Cytotoxicity against tumor cells correlated with the basic structure of the saponins are in accordance with the hemolytical effect. Sugar moieties play an important role for the hemolytical index.

Antineoplastic Agents, Phytogenic↗

Enzymatic degradation of the triterpenoid saponin helianthoside 2.

Helianthoside 2 (1), the main bisdesmosidic saponin of Helianthus annuus L. was converted to the products 2, 3 and 4 by several, optimized enzymatic hydrolysis methods. Monosaccharide units of the acylglycosidic at C-28 of the sapogenin bonded, linear chain oligosaccharide were cleaved, but the branched trisaccharide at C-3 of the aglycone are stable under the conditions used. Compounds 2 and 3 are new triterpenoid glycosides, which were characterized as 28-O-alpha-L-rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranoside (2) and 28-O-alpha-L-arabinopyranoside (3) of 3-O-[alpha-L-rhamnopyranosyl-(1-->3)][beta-D-xylopyranosyl-(1-->4)] beta-D-glucopyranoside of 3 beta,16 alpha-dihydroxy-olean-12-en-28-oic acid.

Carbohydrate Sequence↗

Glucuronidation of amines and other xenobiotics catalyzed by expressed human UDP-glucuronosyltransferase 1A3.

Glucuronide conjugation of xenobiotics containing a tertiary amine moiety represents a unique and important metabolic pathway for these compounds in humans. Previously, human UDP-glucuronosyltransferase (UGT) 1A4 was shown to be an important enzyme for the formation of quaternary ammonium-linked glucuronides. UGT1A3 is 93% identical to UGT1A4 in primary amino acid sequence. We show that human UGT1A3, transiently expressed in human embryonic kidney 293 cells, also catalyzes the N-glucuronidation of primary, secondary, and tertiary amine substrates, such as 4-aminobiphenyl, diphenylamine, and cyproheptadine. In contrast to expressed human UGT1A4, which catalyzes the glucuronidation of amines with high efficiency, glucuronidation of amines catalyzed by UGT1A3 exhibited low efficiency, suggesting that UGT1A3 makes only a limited contribution to the metabolic elimination of these compounds. The reactivity of expressed human UGT1A3 toward hydroxylated and carboxylic acid-containing compounds was also examined. In addition to amines, expressed human UGT1A3 catalyzed the glucuronidation of opioids (e.g. morphine and buprenorphine), coumarins, flavonoids (e.g. naringenin and quercetin), anthraquinones, and small phenolic compounds (e.g. 4-nitrophenol). Drugs containing a carboxylic acid moiety, such as nonsteroidal anti-inflammatory agents (e.g. naproxen and ibuprofen) and fibrates (e.g. ciprofibrate), were substrates for human UGT1A3. In contrast, compounds containing an aliphatic hydroxyl group, such as sapogenins, monoterpenoid alcohols (e.g. menthol and borneol), and androgens, were not conjugated by expressed human UGT1A3. Of the compounds tested, scopoletin, naringenin, and norbuprenorphine appeared to be the best xenobiotic substrates for human UGT1A3.

Amines↗