Metabolism of saikosaponin c and naringin by human intestinal bacteria

By human intestinal bacteria, saikosaponin c was transformed to four metabolites, prosaikogenin E1 (E1) prosaikogenin E2 (E2), prosaikogenin E3 (E3) and saikogenin E. Metabolic time course of saikosaponin c was as follows; in early time, saikosaponin c was converted to E1 and E2, and then these were transformed to saikogenin E via E3. Also, this metabolic pathway was similar to the metabolism of saikosaponin c by rat intestinal bacteria.Bacteroides JY-6 andBacteroides YK-4, the bacteria isolated from human intestinal bacteria, could transform saiko-saponin c to E via E1 (or E2) and E3. However, these bacteria were not able to directly transform E1 and E2 to saikogenin E. Naringin was mainly transformed to naringenin by human intestinal bacteria. The minor metabolic pathway transformed naringin to naringenin via prunin. By JY-6 or YK-4, naringin was metabolized to naringenin only via prunin.     

Metabolism of ginsenoside Re by human intestinal microflora and its estrogenic effect

To understand the relationship between the metabolism and biological activity of ginsenoside Re, a main protopanaxatriol saponin in Panax ginseng C. A. MEYER, its metabolic pathway and estrogenic effect by human intestinal microflora were investigated. All human fecal specimens metabolized ginsenoside Re, mainly to ginsenoside Rh1 and ginsenoside F1, via ginsenoside Rg1, with protopanaxadiol as a minor component. Almost all isolated ginsenoside Re-metabolizing intestinal bacteria (GHIB) also metabolized ginsenoside Re, mainly to ginsenosides Rh1 and F1, via ginsenoside Rg1. Alpha-Rhamnosidase and beta-glucosidase, partially purified from the most potent GHIB, Bacteroides JY-6, hydrolyzed ginsenoside Re and ginsenoside Rg1, respectively; however, they did not hydrolyze ginsenosides Rh1 and F1. These findings suggest that the ginsenosides Rh1 and/or F1 may not be suitable substrates of intestinal bacteria, particularly Bacteroides JY-6. The estrogenic effects of ginsenoside Re and its main metabolites, ginsenosides Rg1 and Rh1, were also investigated. Ginsenoside Rh1 showed the greatest estrogenic effect in human breast carcinoma MCF-7 cells. Based on these findings, the estrogenic effect of ginsenoside Re may be expressed by intestinal microflora.     

Metabolism of 20(S)- and 20(R)-ginsenoside Rg3 by human intestinal bacteria and its relation to in vitro biological activities

When ginsenoside Rg3 was anaerobically incubated with human fecal microflora, all specimens metabolized ginsenoside Rg3 to ginsenoside Rh2 and protopanaxadiol. The main metabolite was ginsenoside Rh2. 20(S)-ginsenoside Rg3 was quickly transformed to 20(S)-ginsenoside Rh2 or 20(S)-protopanaxadiol in an amount 19-fold that compared with the transformation of 20(R)-ginsenoside Rg3 to 20(R)-ginsenoside Rh2 or 20(R)-protopanaxadiol. Among the bacteria isolated from human fecal microflora, Bacteroides sp., Eubacterium sp., and Bifidobacterium sp. metabolized ginsenoside Rg3 to protopanaxadiol via ginsenoside Rh2. However, Fusobacterium sp. metabolized ginsenoside Rg3 to ginsenoside Rh2 alone. Among ginsenoside Rg3 and its metabolites, 20(S)-protopanaxadiol and 20(S)-ginsenoside Rh2 exhibited the most potent cytotoxicity against tumor cell lines, 20(S)- and 20(R)-protopanaxadiols potently inhibited the growth of Helicobacter pylori, and 20(S)-ginsenoside Rh2 inhibited H+/K+ ATPase of rat stomach.     

Metabolism of glycyrrhizin and baicalin by human intestinal bacteria

By human intestinal bacteria, glycyrrhizin (18β-glycyrrhetic acid β-D-glucuronyl α-D-glucuronic acid, GL) and baicalin (baicalein β-D-glucuronic acid) were metabolized to glycyrrhetinic acid and baicalin, respectively. However, α-glucuronidase ofBacteroides JY-6 isolated from human intestinal bacteria hydrolyzed GL or 18β-glycyrrhetinic acid α-D-glucuronic acid to 18β-glycyrrhetic acid but did not baicalin. However,E. coli β-glucuronidase from human intestinal bacteria hydrolyzed baicalin to baicalein, but did not GL. β-Glucuronidase of mammalian tissues hydrolyzed both GL and baicalin.     

Metabolism of kalopanaxsaponin K by human intestinal bacteria and antirheumatoid arthritis activity of their metabolites

When kalopanaxsaponin K (KPK) from Kalopanax pictus was incubated for 24 h at 37 degrees C with human intestinal microflora, KPK was mainly metabolized to kalopanaxsaponin I (KPI) via kalopanaxsaponin H (KPH) rather than via kalopanaxsaponin J (KPJ), and then transformed to kalopanaxsaponin A (KPA) and hederagenin. Bacteroides sp., and Bifidobacterium sp. and Fusobacterium sp. transformed KPK to KPI and KPA and hederagenin via KPH or KPJ. However, Lactobacillus sp. and Streptococcus sp. transformed KPK to KPI, KPA, and hederagenin only via KPJ. The metabolite KPA of KPK showed potent antirheumatoid arthritis activity.     

Antithrombotic and antiallergic activities of rhaponticin from Rhei Rhizoma are activated by human intestinal bacteria

To evaluate the antithrombotic and antiallergic properties of rhaponticin extracted from Rhei Rhizoma, the in vitro and ex vivo inhibitory activities of rhaponticin and its metabolite, rhapontigenin, were measured. These compounds inhibited in vitro ADP- and collagen-induced platelet aggregation. Rhapontigenin was more potent, with IC50 values of 4 and 70 microg/ml, respectively. In ex vivo ADP- and collagen-induced rat platelet aggregation, these compounds also exhibited a potent inhibitory effect. The antiplatelet aggregation effects of rhaponticin and rhapontigenin were more potent than those of aspirin. Rhapontigenin showed significant protection from death due to pulmonary thrombosis in mice. Rhapontigenin also showed the strongest inhibitory activity against beta-hexosaminidase release induced by DNP-BSA. These compounds inhibited PCA reaction in mice. Rhapontigenin intraperitoneally administered showed the strongest inhibitory activity and significantly inhibited PCA at doses of 25 and 50 mg/kg, with inhibitory activities of 48 and 85%, respectively. The inhibitory activity of orally administered rhaponticin was stronger than that of intraperitoneally administered rhaponticin. These results suggest that rhaponticin, in the rhizome of Rhei Rhizoma, is a prodrug that has extensive antiallergic and antithrombotic properties.     

Metabolism of quercitrin by human intestinal bacteria and its relation to some biological activities.

When quercitrin was anaerobically incubated with human intestinal bacteria, quercetin, 3,4-dihydroxyphenylacetic acid and 4-hydroxybenzoic acid were found as metabolites. The main metabolite was quercetin. The bacterium transforming quercitrin to quercetin was Fusobacterium K-60. However, Bacteroides JY-6, which produced alpha-L-rhamnosidase, did not transform quercitrin to quercetin. Among quercitrin and its metabolites, 3,4-dihydroxyphenylacetic acid and 4-hydroxylphenylacetic acid had more potent activity than quercitrin on in vitro anti-platelet aggregation activity, and quercetin and 3,4-dihydroxyphenylacetic acid showed more potent cytotoxicity against tumor cell lines than quercitrin and 4-hydroxylphenylacetic acid.     

Metabolism of swertiamarin from Swertia japonica by human intestinal bacteria

The biotransformation of swertiamarin [1, a seco-iridoid glucoside isolated from Swertia japonica (Schult.) Makino] by human intestinal bacteria was investigated. Three metabolites were isolated and identified as erythrocentaurin (2), 5-hydroxymethylisochroman-1-one (3), and gentianine (4) by spectroscopic methods. Through screening of various defined strains of intestinal bacteria (25 species), it was found that all these species had the ability to metabolize 1 to 2 and 3, whereas only a few species had the ability to produce 4. This is the first report to show that one of the metabolic intermediates of the secoiridoid compound is further transformed to a nitrogen-containing compound through metabolic processes by human intestinal bacteria.     

肠道细菌对天然药物代谢的研究进展Ⅰ

目的：介绍肠道细菌对天然药物代谢的最新研究进展。方法：综述近年来国内外相关文献,对黄酮、皂甙、木脂素、环烯醚萜苷类等天然产物在肠道细菌作用下的代谢情况进行总结归纳。结果：天然产物经肠道细菌代谢后,转化为具有病理或毒理活性的新化合物。结论：许多天然药物以前药形式存在,肠道细菌在其代谢中发挥着至关重要的作用。     

Pharmacokinetics of ginsenoside deglycosylated by intestinal bacteria and its transformation to biologically active fatty acid esters

Ginsenosides are deglycosylated by intestinal bacteria to active forms after oral administration. The present study demonstrated the pharmacodynamics of 20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol (M1), an intestinal bacterial metabolite of ginsenosides, and the in vitro and in vivo antitumor activities of M1-metabolites in comparison with M1 using C57BL/6 mice and Wistar rats. M1 was selectively accumulated into the liver soon after its intravenous administration to mice, and mostly excreted as bile; however, some M1 was transformed to fatty acid ester (EM1) in the liver. EM1 was isolated from rats in a recovery dose of approximately 24 mol%. Structural analysis indicated that EM1 comprised a family of fatty acid mono-esters of M1. Because EM1 was not excreted as bile as M1 was, it was accumulated in the liver longer than M1. Although the cytotoxicity of M1 against B16-F10 melanoma cells was attenuated by fatty acid esterification, EM1 inhibited tumor growth more than M1 in vivo. These results suggest that the fatty acid M1 esters may be the real active principles of ginsenosides in the body.     

Constitutive beta-glucosidases hydrolyzing ginsenoside Rb1 and Rb2 from human intestinal bacteria

When ginsenoside Rb1 and Rb2 were anaerobically incubated with human intestinal microflora, these ginsenosides were metabolized to 20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol (compound K) and 20(S)-protopanaxadiol. Several kinds of intestinal bacteria hydrolyzed these ginsenosides. Eubacterium sp., Streptococcus sp. and Bifidobacterium sp., which more potently hydrolyzed gentiobiose than sophorose, metabolized ginsenoside Rb1 to compound K via ginsenoside Rd rather than gypenoside XVII. However, Fusobacterium K-60, which more potently hydrolyzed sophorose than gentiobiose, metabolized to compound K via gypenoside XVII. Ginsenoside Rb2 was also metabolized to compound K via ginsenoside Rd or compound O by human intestinal microflora. Eubacterium sp., Streptococcus sp. and Bifidobacterium sp. metabolized ginsenoside Rb2 to compound K via ginsenoside Rd rather than compound O. Fusobacterium K-60 metabolized ginsenoside Rb2 to compound K via compound O.     

Metabolism of levamisole, an anti-colon cancer drug, by human intestinal bacteria

1. Anaerobic incubation of levamisole with human intestinal flora resulted in the formation of three thiazole ring-opened metabolites, namely, levametabol-I, II and III. These new hydroxamic lactam-type metabolites were isolated and characterized by various spectroscopic methods. 2. Various pure cultures of human intestinal bacterial strains were shown, by quantitative h.p.l.c. analysis, to have ring-opening ability. Strong metabolizers include Bacteroides and Clostridium spp. Bacterial mixtures prepared from human faeces showed much greater ability to transform levamisole (74% in 48 h) than any pure strain culture. 3. Greatly decreased levamisole-transforming activity was observed with autoclaved bacterial cultures, and no activity was found with broth medium alone. This indicates that metabolism requires the presence of anaerobic bacteria and involves, at least in part, a non-enzymic process.     

Metabolism of liriodendrin and syringin by human intestinal bacteria and their relation toin vitro cytotoxicity

When liriodendrin or syringin was incubated for 24 h with human intestinal bacteria, two metabolites, (+)-syringaresinol-beta-D-glucopyranoside and (+)-syringaresinol, from liriodendrin and one metabolite, synapyl alcohol, from syringin were produced. The metabolic time course of liriodendrin was as follows: at early time, liriodendrin was converted to (+)-syringaresinol-beta-D-glucopyranoside, and then (+)-syringaresinol. The in vitro cytotoxicities of these metabolites, (+)-syringaresinol and synapyl alcohol, were superior to those of liriodendrin and syringin.     

Metabolism of chiisanoside from Acanthopanax divaricatus var. albeofructus by human intestinal bacteria and its relation to some biological activities

The metabolic pathway of chiisanoside isolated from leaves of Acanthopanax divaricatus var. albeofructus (Araliaceae) by human intestinal bacteria and by the protein fraction of leaves of this plant were investigated, and the cytotoxic and anti-rotaviral activities of chiisanoside and its metabolite, chiisanogenin, were assayed. Chiisanogenin was produced as a main metabolite, when chiisanoside were incubated for 15 h with human intestinal bacteria. This metabolic pathway proceeded more potently with the protein fraction than with human intestinal bacteria. The in vitro cytotoxicity of chiisanogenin was superior to that of chiisanoside. H+/K+ ATPase was more potently inhibited by chiisanogenin than by chiisanoside. However, the anti-rotaviral activity of chiisanoside was more potent than that of chiisanogenin.     

Determination of (R,R)-glycopyrronium bromide and its related impurities by ion-pair HPLC

A simple, rapid and specific ion-pair HPLC method for the determination of (R,R)-glycopyrronium bromide and its related impurities is presented, and parameters affecting the chromatographic properties of these compounds are discussed. Optimal analyte separation was achieved on base deactivated Nucleosil at 40 degrees C, using phosphate buffer pH 2.30 with sodium-1-decanesulfonate (0.01 M)/methanol (35/65; v/v) as eluent for isocratic elution at a flow rate 1 ml x min(-1). The analytical assay was validated according to international guidelines. The methodis suitable for in-process control and as stability indicating assay.     

Biotransformation of glycyrrhizin by human intestinal bacteria and its relation to biological activities

The relationship between the metabolites of glycyrrhizin (18beta-glycyrrhetinic acid-3-O-beta-D-glucuronopyranosyl-(1-->2)-beta-D-glucuronide, GL) and their biological activities was investigated. By human intestinal microflora, GL was metabolized to 18beta-glycyrrhetinic acid (GA) as a main product and to 18beta-glycyrrhetinic acid-3-O-beta-D-glucuronide (GAMG) as a minor product. The former reaction was catalyzed by Eubacterium L-8 and the latter was by Streptococcus LJ-22. Among GL and its metabolites, GA and GAMG had more potent in vitro anti-platelet aggregation activity than GL. GA also showed the most potent cytotoxicity against tumor cell lines and the potent inhibitory activity on rotavirus infection as well as growth of Helicobacter pylori. GAMG, the minor metabolite of GL, was the sweetest.     

Metabolism of glycyrrhizin by human intestinal flora.

During the course of experiments on the metabolism of Chinese crude drugs by human intestinal flora, glycyrrhizin, an active component of liquorice, was shown to be hydrolyzed to the aglycone, 18-beta-glycyrrhetic acid, which was then transformed to a new compound, 3-epi-18beta-glycyrrhetic acid. The epimerization of 18beta-glycyrrhetic acid to 3-epi-18beta-glycyrrhetic acid was also shown to be reversible VIA a metabolic intermediate, 3-dehydro-18beta-glycyrrhetic acid.