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PubMed2006

Ginsenoside metabolites, rather than naturally occurring ginsenosides, lead to inhibition of human cytochrome P450 enzymes.

There is still an argument about ginseng-prescription drug interactions. To evaluate the influence on cytochrome P450 (P450) activities of ginseng in the present study, the influence on P450 activities of naturally occurring ginsenosides and their degradation products in human gut lumen was assayed by using human liver microsomes and cDNA-expressed CYP3A4. The results showed that the naturally occurring ginsenosides exhibited no inhibition or weak inhibition against human CYP3A4, CYP2D6, CYP2C9, CYP2A6, or CYP1A2 activities; however, their main intestinal metabolites demonstrated a wide range of inhibition of the P450-mediated metabolism. There was no mechanism-based inhibition found on these P450 isoforms. It is noteworthy that Compound K, protopanaxadiol (Ppd), and protopanaxatriol (Ppt) all exhibited moderate inhibition against CYP2C9 activity, and Ppd and Ppt also exhibited potent competitive inhibition against CYP3A4 activity. We suggest that after oral administration, naturally occurring ginsenosides might influence hepatic P450 activity in vivo via their intestinal metabolites.

Animals↗
PubMed1993

Anti-growth effects with components of Sho-saiko-to (TJ-9) on cultured human hepatoma cells.

The present study was undertaken to investigate the effects and the mechanism of the components of Sho-saiko-to (baicalein, baicalin, saikosaponin-a, saikosaponin-c, ginsenoside Rb1, ginsenoside Rg1) on cultured human hepatoma cells (HuH-7). Cell cycle analysis was carried out with flow cytometry and the bromodeoxyuridine (BrdU)-labelling method. The results showed that baicalein, baicalin and saikosaponin-a inhibited cell proliferation dose-dependently but independently of the cell cycle. Furthermore, it was found that saikosaponin-a possesses a strong cell-killing effect. On the other hand, saikosaponin-c, ginsenoside Rb1 and ginsenoside Rg1 had no effect on cell proliferation.

Antineoplastic Agents↗
PubMed1995

Effects of nine active ingredients in Chinese herbal medicine sho-saiko-to on 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide mutagenicity.

The antimutagenic effects of nine active compounds in the Chinese herbal medicine "sho-saiko-to" on mutagenesis induced by a direct-acting mutagen, 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide (AF-2) were investigated in Salmonella typhimurium, strain TA100. The active compounds examined were classified into two major groups, saponins and flavonoids, the former comprising glycyrrhizin, saikosaponins a, c, and d, and ginsenosides Rb1 and Rg1, and the latter, baicalin, baicalein and wogonin. Saikosaponin a and ginsenoside Rb1 were found to reduce the mutagenicity of AF-2 significantly when applied post-AF-2-treatment in the Salmonella mutagenicity assay. Ginsenoside Rb1 also decreased the mutagenic activity of AF-2 in a simultaneous treatment protocol. The results indicate that saikosaponin a and ginsenoside Rb1 may enhance DNA repair, and ginsenoside Rb1 may also have the ability to inactivate the mutagenic activity of AF-2 directly. On the other hand, saikosaponin d and baicalin showed a slight enhancing effect. None of the compounds, except baicalein, showed any toxic effect on the test strain. These findings may be useful for the development of chemopreventive agents.

Animals↗
PubMed1995

Saikosaponin A-induced cell death of a human hepatoma cell line (HuH-7): the significance of the 'sub-G1 peak' in a DNA histogram.

Saikosaponin A (SSA) induced cell death in the human hepatoma cell line (HuH-7) was investigated. Shortly after exposure to SSA, a DNA histogram showed a 'sub-G1 peak', which was recently reported as suggestive of apoptosis by other researchers. However, the electrophoresis of DNA indicated that such was not the case in the present experiment. The decreased intake of rhodamine 123 and the swelling of mitochondria were remarkable shortly after SSA exposure. These data seem to support the idea that the sub-G1 peak represents necrosis rather than apoptosis. Interestingly, the DNA electrophoresis revealed the smear pattern of small DNA fragments shortly after SSA-exposure, although it did not show the apoptotic ladder pattern. This finding and the appearance of the 'sub-G1 peak' is thought to have been a result of the degradation of the nuclear DNA in the early stages of cell death. Because these findings are different not only from apoptosis, but also from typical necrosis, a distinct mechanism of cell death caused by SSA is suggested.

Apoptosis↗
PubMed1997

Suppressive effects of sairei-to on monoclonal antibody 1-22-3-induced glomerulonephritis: analysis of effective components.

The effects of traditional Chinese medicine (Sairei-to) on experimental glomerulonephritis induced in rats by monoclonal antibody (mAb) 1-22-3 injection was examined. The level of proteinuria in the Sairei-to-treated group was significantly lower than that in the PBS treated group. This suppressive effect was caused by the major component of Sairei-to, Syo-saiko-to but not by another component, Gorel-san. The suppressive effect of Syo-saiko-to was identified in its components (Bupleuri radix, Pinelliae tuber and Zingiberis rhizoma), but not in the other combined components (Ginseng radix and Zizyphi fructus). Further study revealed that the suppressive effects of the combined components were mainly derived from Bupleuri radix. It was demonstrated that the actual active ingredient is probably Saikosaponin-d. Light microscopy revealed that Sairei-to and its effective components suppressed the proliferation of mesangial cells and mesangial matrix expansion. Semiquantitative morphological studies of glomerular lesions on the eighth day showed that Syo-saiko-to and its combined components (Bupleuri radix, Zingiberis rhizoma and Pinelliae tuber) suppressed mesangial matrix expansion significantly compared with phosphate-buffered saline control groups (matrix score: 28.0 +/- 19.1 vs 102.3 +/- 14.1; 30.9 +/- 30.1 vs 102.3 +/- 14.1, P < 0.005, respectively). It was concluded that Saikosaponin-d, as well as Bupleuri radix, Syo-saiko-to and Sairei-to can suppress proteinuria and morphological changes in the rat glomerulonephritis model induced by mAb 1-22-3.

Animals↗
PubMed2006

Ginsenoside 20(S)-protopanaxadiol inhibits the proliferation and invasion of human fibrosarcoma HT1080 cells.

Ginsenoside 20(S)-protopanaxadiol, one of metabolites of ginseng saponins, has been well characterized to possess the pleiotropic anticancer capabilities in several cancer cell lines. The object of this study was to investigate the effects of ginsenoside 20(S)-protopanaxadiol on the invasion in vitro and the expression of matrix metalloproteinase-2 in human fibrosarcoma HT1080 cells in absence of cytotoxicity. Our results showed that ginsenoside 20(S)-protopanaxadiol exerted a concentration-dependent inhibitory effect on the proliferation of HT1080 cells (IC50 was 76.78+/-2.24 microM, 48 hr). Treatment with 20(S)-protopanaxadiol significantly declined the invasive capacity of HT1080 cells compared to the control cells (P<0.01) in the in vitro invasion assay. Further analysis with gelatin zymography and western blotting revealed that both the activity and the expression of matrix metalloproteinase-2 decreased dramatically in a concentration-dependent manner (P<0.01). Taken together, these results indicated that ginsenoside 20(S)-protopanaxadiol is able to inhibit the invasiveness of HT1080 cells significantly in vitro and this action may be primarily due to down-regulating the expression of matrix metalloproteinase-2. Ginsenoside 20(S)-protopanaxadiol, a metabolite of ginseng, may be applied as a potential therapeutic agent in the prevention and treatment of cancer.

Antineoplastic Agents, Phytogenic↗
PubMed1993

Effects of saiboku-to (TJ-96) on the production of platelet-activating factor in human neutrophils.

Platelet-activating factor (PAF) has been recognized as an important chemical mediator in allergic and inflammatory reactions. Evidence suggests that PAF is deeply involved in the pathogenesis of bronchial asthma, in which PAF induces profound bronchospasms, increased vascular permeability, and eosinophil/neutrophil accumulation in the respiratory tract. The precise pharmacologic mechanisms of Kampo preparations are still obscure, but extensive experience has established their clinical effectiveness for the treatment of patients with allergic and inflammatory disorders. We tried to examine the effects of Saiboku-to (TJ-96), a Kampo prescription, on in vitro PAF production by human neutrophils because this preparation is widely used for the management of patients with bronchial asthma and bronchitis. Saibokuto inhibited in vitro PAF production in a dose-dependent manner. Among the major natural components of Saiboku-to, saiko (Bupleuri radix) and kanzo (Glycyrrhizae radix) showed inhibitory effects on PAF production, whereas ohgon (Scutellariae radix) had no inhibitory effect. Saikosaponin a and c, purified elements extracted from saiko, showed no inhibitory effects, but saikosaponin d and glycyrrhizin, extracted from kanzo, inhibited PAF production dose-dependently. Further studies are needed to evaluate the clinical significance of Kampo medicines in allergic diseases, but our present results suggest that the pharmacologic benefit of Saiboku-to is partially due to its inhibitory effect on PAF production.

Drugs, Chinese Herbal↗
PubMed1988

Vaccination as a possible means of preventing lantana poisoning.

The toxic triterpene acids lantadene A and lantadene B were isolated from Lantana camara and conjugated to bovine serum albumen or haemocyanin. The conjugates were emulsified with complete Freund's adjuvant and injected into sheep and cattle. Vaccinated animals produced antibodies against the toxic compounds. Cholestasis was less severe in vaccinated than in non-vaccinated sheep challenged with a toxic dose of lantana. The results indicated a mild protective effect of vaccination against the hepatotoxic effects of lantana toxins.

Animals↗
PubMed1985

Effects of saikosaponin-d on enhanced CCl4-hepatotoxicity by phenobarbitone.

The effects of saikosaponin-d extracted from the roots of Buplerum falcatum L. on increased toxicity of CCl4 and increased activities of microsomal enzymes induced by phenobarbitone have been examined. Saikosaponin-d showed protection against the CCl4-hepatotoxicity enhanced by phenobarbitone. It also inhibited increases in the content of cytochrome P450 and NADPH-cytochrome c reductase activity, which are induced by the phenobarbitone treatment, but the spectral characteristics of P450 were not altered. The rate of microsomal lipid peroxidation by NADPH and CCl4 was significantly lowered in-vitro in rats pretreated with phenobarbitone and saikosaponin-d compared with those pretreated with phenobarbitone alone.

Alanine Transaminase↗
PubMed2006

In vitro characterization of lamotrigine N2-glucuronidation and the lamotrigine-valproic acid interaction.

Studies were performed to investigate the UDP-glucuronosyltransferase enzyme(s) responsible for the human liver microsomal N2-glucuronidation of the anticonvulsant drug lamotrigine (LTG) and the mechanistic basis for the LTG-valproic acid (VPA) interaction in vivo. LTG N2-glucuronidation by microsomes from five livers exhibited atypical kinetics, best described by a model comprising the expressions for the Hill (1869 +/- 1286 microM, n = 0.65 +/- 0.16) and Michaelis-Menten (Km 2234 +/- 774 microM) equations. The UGT1A4 inhibitor hecogenin abolished the Michaelis-Menten component, without affecting the Hill component. LTG N2-glucuronidation by recombinant UGT1A4 exhibited Michaelis-Menten kinetics, with a Km of 1558 microM. Although recombinant UGT2B7 exhibited only low activity toward LTG, inhibition by zidovudine and fluconazole and activation by bovine serum albumin (BSA) (2%) strongly suggested that this enzyme was responsible for the Hill component of microsomal LTG N2-glucuronidation. VPA (10 mM) abolished the Hill component of microsomal LTG N2-glucuronidation, without affecting the Michaelis-Menten component or UGT1A4-catalyzed LTG metabolism. Ki values for inhibition of the Hill component of LTG N2-glucuronidation by VPA were 2465 +/- 370 microM and 387 +/- 12 microM in the absence and presence, respectively, of BSA (2%). Consistent with published data for the effect of fluconazole on zidovudine glucuronidation by human liver microsomal UGT2B7, the Ki value generated in the presence of BSA predicted the magnitude of the LTG-VPA interaction reported in vivo. These data indicate that UGT2B7 and UGT1A4 are responsible for the Hill and Michaelis-Menten components, respectively, of microsomal LTG N2-glucuronidation, and the LTG-VPA interaction in vivo arises from inhibition of UGT2B7.

Anticonvulsants↗
PubMed2003

Degradation of ginsenosides in humans after oral administration.

Even though the degradation of ginsenosides has been thoroughly studied in animals and in vitro using acids, enzymes, and intestinal bacteria, knowledge concerning the systemic availability of ginsenosides and their degradation products in humans is generally lacking. Therefore, the attention in this article is focused on the identification of ginsenosides and their hydrolysis products reaching the systemic circulation in man. This is of great importance in understanding clinical effects, preventing herb-drug interactions, and optimizing the biopharmaceutical properties of ginseng preparations. Using a sensitive mass spectrometric method, which is specific for the identification of ginsenosides in complex biological matrices, the degradation pathway of ginsenosides in the gastrointestinal tract of humans could be elucidated following the oral administration of ginseng. Within the frame of a pilot study, human plasma and urine samples of two subjects were screened for ginsenosides and their possible degradation products. In general, the urine data coincided well with the plasma data. In both volunteers the same hydrolysis products, which are not originally present in the Ginsana extract (Pharmaton S.A., Lugano, Switzerland) ingested, were identified in plasma and urine. It was shown that two hydrolysis products of the protopanaxatriol ginsenosides, namely G-Rh1 and G-F1 may reach the systemic circulation. In addition, compound-K, the main intestinal bacterial metabolite of the protopanaxadiol ginsenosides, was detected in plasma and urine. These products are probably responsible for the action of ginseng in humans. In opposition to previous reports, G-Rb1 was identified in plasma and urine of one subject.

Administration, Oral↗
PubMed2004

Ginsenosides 20(S)-protopanaxadiol and Rh2 reduce cell proliferation and increase sub-G1 cells in two cultured intestinal cell lines, Int-407 and Caco-2.

Ginsenosides derived from 20(S)-protopanaxatriol (PT) and 20(S)-protopanaxadiol (PD) groups had similar characteristic cytotoxic effects on the growth of two intestinal cells lines, Int-407 and Caco-2. Pure Rh2, a ginsenoside structurally related to PD, inhibited intestinal cell growth at greater than twice the concentration of PD, while Rh1, a ginsenoside structurally related to aglycone PT, had no cytotoxic effect. Concentrations causing growth inhibition of 50% of cells (LC50) for the compounds PD, PT, and Rh2 were 23, 26, and 53 microg/mL, respectively, for Int-407 cells. In comparison, the LC50 for PD and PT was determined to be 24 microg/mL, and that for Rh2 was 55 microg/mL in Caco-2 cells. A standardized North American ginseng extract with a known ginsenosides composition did not induce cytotoxicity in either of the intestinal cell lines. Cell cycle analysis showed characteristically different (P = 0.05) effects of ginsenosides PD, Rh2, and PT in both cell lines. Rh2 treatment of Int-407 caused a significantly (P = 0.05) higher production of sub-G1 (apoptotic) cells (35% +/- 1%) compared with untreated cells (14% +/- 0.3%) after 24 h. PD and Rh2 treatments were both significantly (P < 0.05) higher in apoptotic cells than in untreated cells after 48 and 72 h. Similar results were obtained for treatment of Caco-2 cells. Lactate dehydrogenase (LDH) activity in both cell lines was similar for PD and Rh2 and higher (P = 0.05) than for PT treatment at most time periods. These results show a specific structure-function relationship for bioactive ginsenosides in two contrasting intestinal cell types.

Apoptosis↗
PubMed1995

Studies on the agronomic characteristics, yield, and saikosaponin content of two Bupleurum species in Taiwan.

Two Bupleurum species (Bupleurums spp.), i.e., B. falcatum L. cv. Tainung No. 1 and B. kaoi Liu, Chao, et Chuang, were compared for their differences in seed germination, plant characteristics and root yield, and saikosaponin content. Experimental data showed that the most suitable temperature for seed germination of the two species was 16 degrees C. Two treatments, cold stratification at 4 degrees C for 8 weeks and presoaking by running water for 2 days, resulted in higher germination rates. Tainung No. 1 possessed a higher 1,000-seed weight than B. kaoi. However, field survival rate was higher for B. kaoi than for Tainung No.1. Results from field experiments also revealed that stem diameter, leaf width and fresh weight of various plant parts except the root were superior for Tainung No. 1 to B. kaoi. On the contrary, tiller number and root diameter and weight of B. kaoi were higher than those of Tainung No. 1. Harvest data and elevation had significant effects on the agronomic performance of the two Bupleurum spp. Measurements of most traits of the 6 month-old plants were superior to those of the 3 and 10 month-old plants. Cultivation at higher elevation (850 m) favored the development of leaf weight and root length, while cultivation at lower elevation (85 m) facilitated the development of plant height, root diameter, and root weight. Analysis of saikosaponin concentration in the root tissue revealed that average contents of 3.19 and 3.80 mg/g, respectively, for plants grown at the elevations of 850 m and 85 m. Comparison between the two species showed no significant difference in saikosaponin content, ranging from 3.45 to 3.55 mg/g.

Bupleurum↗
PubMed2005

Cyclooxygenase-2 inhibits novel ginseng metabolite-mediated apoptosis.

Recently, a novel intestinal bacterial metabolite of ginseng protopanaxadiol saponins, i.e., 20-O-(beta-D-glucopyranosyl)-20(S)-protopanaxadiol (IH-901), has been reported to induce apoptosis in a variety of cancer cells. Here we show a differential effect of IH-901 on several cell types. Exposure to IH-901 for 48 hours at a supposedly subapoptotic concentration of 40 mumol/L led to both apoptotic cell death and G1 arrest in Hep3B cells, but only resulted in G1 arrest in MDA-MB-231, Hs578T, and MKN28 cells. Additionally, the treatment of MDA-MB-231, but not of Hep3B, with IH-901 up-regulated cyclooxygenase-2 (COX-2) mRNA (2 hours) and protein (6 hours), and enhanced the production of prostaglandin E2. In MDA-MB-231 cells, IH-901 induced the sustained activation of extracellular signal-regulated kinase (ERK), whereas inhibition of mitogen-activated protein/ERK kinase blocked IH-901-mediated COX-2 induction and resulted in apoptosis, suggesting the involvement of an ERK-COX-2 pathway. Combined treatment with IH-901 and nonsteroidal anti-inflammatory drugs inhibited COX-2 enzyme and induced apoptosis in MDA-MB-231 and Hs578T cells. Adenovirus-mediated COX-2 small interfering RNAs also effectively inhibited COX-2 protein expression and enhanced IH-901-mediated apoptosis without inhibiting ERK 1/2 phosphorylation, thus providing direct evidence that COX-2 is an antiapoptotic molecule. Moreover, IH-901-mediated G1 arrest resulted from an increase in p27Kip1 mRNA and protein expression followed by a decrease in CDK2 kinase activity that was concurrent with the hypophosphorylation of Rb and p130. In conclusion, IH-901 induced both G1 arrest and apoptosis, and this apoptosis could be inhibited by COX-2 induction.

Anti-Inflammatory Agents, Non-Steroidal↗