Ginsenoside Metabolites, Rather Than Naturally Occurring Ginsenosides, Lead to Inhibition of Human Cytochrome P450 Enzymes

Liu, Yong; Jiangwei, Zhang; Li, Wei; Ma, Hong; Sun, Jie; Deng, Mingke; Yang, Ling

doi:10.1093/toxsci/kfj164

Cited by 129 publications

(90 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Especially, the metabolites of ginsenosides that are formed by enteric bacteria have been focused on for their pharmacological activities. Among them, compound K (C-K) is known to be formed by enteric bacterial fermentation of Rb1, Rb2 and RC, and C-K has been reported to suppress tumor metastasis and inflammatory responses (6,7). Another ginsenoside Rh2, a metabolite of Rg3, is also known for its tumor suppression by inducing apoptosis or retarding growth signals (8).…”

Section: Proapoptotic Ginsenosides Compound K and Rh2 Enhance Fas-indmentioning

confidence: 99%

Proapoptotic Ginsenosides Compound K and Rh2 Enhance Fas-induced Cell Death of Human Astrocytoma Cells Through Distinct Apoptotic Signaling Pathways

Choi

2009

Cancer Res Treat

View full text Add to dashboard Cite

I n t r o d u c t i o nGlioblastoma multiforme (GBM) is the most malignant and common brain tumor and it comprises ~23% of all primary brain tumors in adults. These malignancies are refractory to all the current therapeutic approaches, including surgery, radiotherapy and chemotherapy. Fas (CD95 or APO-1) is a member of the TNF/NGF receptor family, and Fas induces caspase-dependent apoptotic death in various transformed cells (1,2). Fas ligation with natural ligand or agonistic anti-Fas antibody is followed by recruitment of proapoptotic adaptor molecules such as Fas-associated death domain (FADD) to transduce the apoptotic signals through the caspase cascades (3). In some cells, Fas efficiently activates caspase-8 and it subsequently activates caspase-3 or 7, while other types of Fasinduced apoptosis are mediated by cytochrome-C release from the mitochondria and this is inhibited by the over-expression of antiapoptotic bcl-2 family members (4).Panax Ginseng is known for its biological and pharmacological activities such as its anti-cancer, anti-aging, anti-inflammatory and anti-oxidant properties in the nervous, immune and circulatory systems (5). These diverse physiological activities of ginseng are mainly mediated by saponin, which is a ginsenoside. Especially, the metabolites of ginsenosides that are formed by enteric bacteria have been focused on for their pharmacological activities. Among them, compound K (C-K) is known to be formed by enteric bacterial fermentation of Rb1, Rb2 and RC, and C-K has been reported to suppress tumor metastasis and inflammatory responses (6,7). Another ginsenoside Rh2, a metabolite of Rg3, is also known for its tumor suppression by inducing apoptosis or retarding growth signals (8).We have previously shown that human malignant astrocytoma cells are quite resistant to Fas-induced apoptosis even though these Cancer Res Treat. 2009;41(1):36-44 Purpose Malignant astrocytomas are among the commonest primary brain tumors and they have a grave prognosis, and so there is an urgent need to develop effective treatment. In this study, we investigated the molecular mechanisms that are responsible for the anti-tumor effect of ginsenosides on human astrocytoma cells. Materials and MethodsWe tested 13 different ginsenosides for their anti-tumor effect on human malignant astrocytoma cells in conjunction with Fas stimulation. In addition, the cell signaling pathways were explored by using pharmacological inhibitors and performing immunoblot analysis. DCF-DA staining and antioxidant experiments were performed to investigate the role of reactive oxygen species as one of the apoptosis-inducing mechanisms. ResultsAmong the 13 different ginsenoside metabolites, compound K and Rh2 induced apoptotic cell death of the astrocytoma cells in a caspase-and p38 MAPK-dependent manner, yet the same treatment had no cytotoxic effect on the primary cultured human astrocytes. Combined treatment with ginsenosides and Fas ligand showed a synergistic cytotoxic effect, which was mediated by the reduction of intracell...

show abstract

Section: Proapoptotic Ginsenosides Compound K and Rh2 Enhance Fas-indmentioning

confidence: 99%

Proapoptotic Ginsenosides Compound K and Rh2 Enhance Fas-induced Cell Death of Human Astrocytoma Cells Through Distinct Apoptotic Signaling Pathways

Choi

2009

Cancer Res Treat

View full text Add to dashboard Cite

show abstract

“…Known inhibitors were run in parallel as positive controls: furafylline for CYP1A2, sulfaphenazole for CYP2C9, quinidine for CYP2D6, and ketoconazole for CYP3A4. The (Liu et al, 2006). The K i values were determined by fitting the enzyme activity substrate concentration data at various inhibitor concentrations to the equations for competitive inhibition, noncompetitive inhibition, and mixed-type inhibition.…”

Section: Inhibitory Effects Of Seven Danshen Components On P450smentioning

confidence: 99%

Inhibitory Effects of Seven Components of Danshen Extract on Catalytic Activity of Cytochrome P450 Enzyme in Human Liver Microsomes

Qiu¹,

Zhang²,

Sun³

et al. 2008

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:The potential for herb-drug interactions has recently received greater attention worldwide, considering the fact that the use of herbal products becomes more and more widespread. The goal of this work was to examine the potential for the metabolism-based drug interaction arising from seven active components (danshensu, protocatechuic aldehyde, protocatechuic acid, salvianolic acid B, tanshinone I, tanshinone IIA, and cryptotanshinone) of danshen extract. Probe substrates of cytochrome P450 enzymes were incubated in human liver microsomes (HLMs) with or without each component of danshen extract. IC 50 and K i values were estimated, and the types of inhibition were determined. Among the seven components of danshen extract, tanshinone I, tanshinone IIA, and cryptotanshinone were potent competitive inhibitors of CYP1A2 (K i ‫؍‬ 0.48, 1.0, and 0.45 M, respectively); danshensu was a competitive inhibitor of CYP2C9 (K i ‫؍‬ 35 M), and cryptotanshinone was a moderate mixed-type inhibitor of CYP2C9 (K i ‫؍‬ 8 M); cryptotanshinone inhibited weakly and in mixed mode against CYP2D6 activity (K i ‫؍‬ 68 M), and tanshinone I was a weak inhibitor of CYP2D6 (IC 50 ‫؍‬ 120 M); and protocatechuic aldehyde was a weak inhibitor of CYP3A4 (IC 50 ‫؍‬ 130 and 160 M for midazolam and testosterone, respectively). These findings provided some useful information for safe and effective use of danshen preparations in clinical practice. Our data indicated that it was necessary to study the in vivo interactions between drugs and pharmaceuticals with danshen extract.

show abstract

“…Besides, the deglycosylation of saponin to aglycone can also strongly increase the inhibitory effects towards CYPs. Liu et al [21] found that naturally occurring ginsenosides exhibited no inhibition or weak inhibition against human CYPs, while their main intestinal metabolites demonstrated a wide range of inhibition of the P450-mediated metabolism. However, different from the above articles, it is interesting that the intestinal metabolites of icariin exhibited a different inhibition profile compared with icarrin [22].…”

Section: Discussionmentioning

confidence: 99%

Evaluation and Comparison of the Inhibition Effect of Astragaloside IV and Aglycone Cycloastragenol on Various UDP-Glucuronosyltransferase (UGT) Isoforms

Ran

Zhang

et al. 2016

Molecules

View full text Add to dashboard Cite

As one of the main active ingredients from Radix Astragali (RA), orally dosed astragaloside IV (AST) is easily transformed to sapogenin-cycloastragenol (CAG) by deglycosylation in the gastrointestinal tract. Because the potential adverse effects of AST and CAG remain unclear, the present study in this article was carried out to investigate the inhibition effects of AST and CAG on UDP-glucuronosyltransferases (UGTs) to explore potential clinical toxicity. An in vitro UGTs incubation mixture was employed to study the inhibition of AST and CAG towards UGT isoforms. Concentrations of 100 µM for each compound were used to initially screen the inhibitory efficiency. Deglycosylation of AST to CAG could strongly increase the inhibitory effects towards almost all of the tested UGT isoforms, with an IC 50 of 0.84 µM and 11.28 µM for UGT1A8 and UGT2B7, respectively. Ulteriorly, the inhibition type and kinetics of CAG towards UGT1A8 and UGT2B7 were evaluated depending on the initial screening results. Data fitting using Dixon and Lineweaver-Burk plots demonstrated that CAG competitively inhibited UGT1A8 and noncompetitively inhibited UGT2B7. From the second plot drawn with the slopes from the Lineweaver-Burk plot versus the concentrations of CAG, the inhibition constant (Ki) was calculated to be 0.034 µM and 20.98 µM for the inhibition of UGT1A8 and UGT2B7, respectively. Based on the [I]/Ki standard ([I]/Ki < 0.1, low possibility; 1 > [I]/Ki > 0.1, medium possibility; [I]/Ki > 1, high possibility), it was successfully predicted here that an in vivo herb-drug interaction between AST/CAG and drugs mainly undergoing UGT1A8-or UGT2B7-catalyzed metabolism might occur when the plasma concentration of CAG is above 0.034 µM and 20.98 µM, respectively.

show abstract

Ginsenoside Metabolites, Rather Than Naturally Occurring Ginsenosides, Lead to Inhibition of Human Cytochrome P450 Enzymes

Cited by 129 publications

References 32 publications

Proapoptotic Ginsenosides Compound K and Rh2 Enhance Fas-induced Cell Death of Human Astrocytoma Cells Through Distinct Apoptotic Signaling Pathways

Proapoptotic Ginsenosides Compound K and Rh2 Enhance Fas-induced Cell Death of Human Astrocytoma Cells Through Distinct Apoptotic Signaling Pathways

Inhibitory Effects of Seven Components of Danshen Extract on Catalytic Activity of Cytochrome P450 Enzyme in Human Liver Microsomes

Evaluation and Comparison of the Inhibition Effect of Astragaloside IV and Aglycone Cycloastragenol on Various UDP-Glucuronosyltransferase (UGT) Isoforms

Contact Info

Product

Resources

About