Microsomal Cytochrome P450-Mediated Metabolism of Protopanaxatriol Ginsenosides: Metabolite Profile, Reaction Phenotyping, and Structure-Metabolism Relationship

Hao, Haiping; Li, Lai; Zheng, Chaonan; Wang, Qiong; Yu, Guo; Zhou, Xueyan; Wu, Liang; Gong, Ping; Wang, Guangji

doi:10.1124/dmd.110.033845

Cited by 57 publications

(42 citation statements)

References 46 publications

(39 reference statements)

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“…Our results showed that its contribution to Rb1 depletion can be negligible due to the extremely poor capacity of Rb1 metabolism in hepatic and intestinal microsomes. Similar results were found in protopanaxatriol-type ginsenosides (Hao et al, 2010). Compared with some deglycosylated metabolites such as Rh1 and Rf, Re and Rb1 were not easily metabolized by CYP3A4, implying that efficiency of oxygenation was reduced due to sugar moieties at the C-20 site.…”

Section: Discussionsupporting

confidence: 71%

Combined Contribution of Increased Intestinal Permeability and Inhibited Deglycosylation of Ginsenoside Rb1 in the Intestinal Tract to the Enhancement of Ginsenoside Rb1 Exposure in Diabetic Rats after Oral Administration

Liu

Guo

et al. 2015

Drug Metab Dispos

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Panax ginseng is becoming a promising antidiabetic herbal medication. As the main active constituents of Panax ginseng, ginsenosides are well known, poorly absorbed chemicals. However, the pharmacokinetic behavior of ginsenosides under diabetic conditions is not fully understood. This study aimed to explore the alterations and potential mechanisms of pharmacokinetic behavior of ginsenoside Rb1 in diabetic rats compared with normal rats and rats fed a high-fat diet. Systemic exposure (area under the concentration-time curve extrapolated from zero to infinity) was significantly increased in diabetic rats after oral administration of Rb1. Oral bioavailability of Rb1 was significantly higher in diabetic rats (2.25%) compared with normal rats (0.90%) and rats fed a highfat diet (0.78%). Further studies revealed that increased Rb1 exposure in diabetic rats may be mainly attributed to increased Rb1 absorption via the intestine and inhibited Rb1 deglycosylation by the intestinal microflora. Neither metabolic enzymes nor drug transporters displayed appreciable effects on Rb1 disposition. The transport of paracellular markers (fluorescein sodium and fluorescein isothiocyanate-dextran of 4 kDa) as well as Rb1 itself across the Caco-2 monolayer cultured with diabetic serum was promoted, demonstrating that increased paracellular permeability of the Caco-2 monolayer may benefit intestinal Rb1 absorption. In addition, Rb1 exposure was decreased in diabetic rats after Rb1 intravenous administration, which may result from increased Rb1 urinary excretion. In conclusion, Rb1 oral exposure was significantly increased under diabetic conditions, which is of positive significance to clinical treatment. The potential mechanism may be associated with the combined contribution of increased gut permeability and inhibited deglycosylation of ginsenoside Rb1 by intestinal microflora.

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Section: Discussionsupporting

confidence: 71%

Combined Contribution of Increased Intestinal Permeability and Inhibited Deglycosylation of Ginsenoside Rb1 in the Intestinal Tract to the Enhancement of Ginsenoside Rb1 Exposure in Diabetic Rats after Oral Administration

Liu

Guo

et al. 2015

Drug Metab Dispos

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“…Ginseng saponin extract (GSE); ginsenoside Rb1, Rb2, Rc, Rd, Re, Rg1, Rg3, Rh1, Rh2, CK, protopanaxadiol (PPD); and protopanaxatriol (PPT) were purchased from Hongjiu Biotech Co. Ltd. (Jilin, China). The contents of ginsenosides (Rb 1 11.2%, Rb 2 11.1%, Rc 10.5%, Rd 7.7%, Re 8.9%, Rf 0.9%, Rg1 3.3%, Rg2 1.4%, and Rh1 0.2%) were determined using a validated liquid chromatography-mass spectrometry method in our laboratory (Hao et al, 2010). Rifampicin (RIF) was purchased from Sigma-Aldrich (Shanghai, China).…”

Section: Methodsmentioning

confidence: 99%

Ginsenosides Regulate PXR/NF-κB Signaling and Attenuate Dextran Sulfate Sodium–Induced Colitis

et al. 2015

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Pregnane X receptor (PXR) activation exhibits anti-inflammatory effects via repressing nuclear factor-kB (NF-kB); however, its overactivation may disrupt homeostasis of various enzymes and transporters. Here we found that ginsenosides restore PXR/NFkB signaling in inflamed conditions without disrupting PXR function in normal conditions. The effects and mechanisms of ginsenosides in regulating PXR/NF-kB signals were determined both in vitro and in vivo. Ginsenosides significantly inhibited NFkB activation and restored the expression of PXR target genes in tumor necrosis factor-a-stimulated LS174T cells. Despite not being PXR agonists, ginsenosides repressed NF-kB activation in a PXR-dependent manner. Ginsenosides significantly increased the physical association between PXR and the NF-kB p65 subunit and thereby decreased the nuclear translocation of p65. Ginsenoside Rb1 and compound K (CK) were major bioactive compounds in the regulating PXR/NF-kB signaling. Consistently, ginsenosides significantly attenuated dextran sulfate sodium-induced experimental colitis, which was associated with restored PXR/NF-kB signaling. This study indicates that ginsenosides may elicit antiinflammatory effects via targeting PXR/NF-kB interaction without disrupting PXR function in healthy conditions. Ginsenoside Rb1 and CK may serve as leading compounds in the discovery of new drugs that target PXR/NF-kB interaction in therapy for inflammatory bowel disease.

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“…Oxygenated metabolites were also identified for Rg3, Rh2, and Rd [49][50][51] in rats and for Ppt in rat hepatic microsomes [52]. In addition, oxygenated metabolism on the C20 aliphatic branch chain was identified as the predominant metabolic pathway of Ppt ginsenosides in both human and rat hepatic microsomes, and CYP3A4 was the predominant isozyme responsible for the oxygenated metabolism of Ppt ginsenosides [53]. Such evidence strongly suggests that the microsomal cytochrome P450 enzymes may play an important role in the systematic disposition of ginsenosides which would affect final exposure in the systemic circulation after oral ingestion.…”

Section: Identification Of Phytochemicals As Sub-strates Of Cypmentioning

confidence: 96%

Interactions between Phytochemicals from Traditional Chinese Medicines and Human Cytochrome P450 Enzymes

Wu¹,

Ai²,

Liu³

et al. 2012

CDM

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Traditional Chinese medicine (TCM) formulas with fixed combinations rely on "sovereign, minister, assistant and guide" and fuzzy mathematical quantitative law, leading to greater challenges for the identification of active ingredients. Transformation and metabolic studies involving the Phase I drug-metabolizing enzyme cytochrome P450 (CYP) might potentially solve some of these challenges. The pharmacological effects can not be attributed to one active ingredient in TCMs, but integrated effects resulting from the combined actions of multiple ingredients. However, it is only after long-term administration that most ingredients exert their actions, which can result in prolonged exposure to herbs in vivo. Therefore, interactions between herbal compounds and CYPs appear to be inevitable. Yet unlike Western drugs, experimental determination of the absorption and disposition properties is not commonly carried out for TCMs. Moreover, the use of TCM as injections is an innovation aimed to improve efficiency in extensive clinical use in Mainland China. Therefore, in recent years, cases of adverse drug reactions (ADR) mainly concerning allergic reactions involving TCMs such as ShenMai injection and QingKaiLing injection have been reported, which have attracted attention with regard to the legal responsibilities for TCM approval. The lack of information on the ADME characteristics, especially the metabolic stability and interaction potential between CYPs and herbs, increases ADR occurrence due to TCMs. In this article, we review the most common herbs used in TCM prescriptions and fixed combinations of their usable frequency, and summarize the current understanding of the ability of phytochemical ingredients to act as substrates, inhibitors or inducers of human CYP enzymes, through which the key role of CYP enzymes on the herb disposition and toxicity is highlighted. The potential interaction between herbal phytochemicals and CYP enzymes dominates the target exposure, which further helps to elucidate the herbal pharmacological basis, assess the individual toxic risk of herbal remedies and gain mechanistic insight into herb-drug interactions (HDIs).

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Microsomal Cytochrome P450-Mediated Metabolism of Protopanaxatriol Ginsenosides: Metabolite Profile, Reaction Phenotyping, and Structure-Metabolism Relationship

Cited by 57 publications

References 46 publications

Combined Contribution of Increased Intestinal Permeability and Inhibited Deglycosylation of Ginsenoside Rb1 in the Intestinal Tract to the Enhancement of Ginsenoside Rb1 Exposure in Diabetic Rats after Oral Administration

Combined Contribution of Increased Intestinal Permeability and Inhibited Deglycosylation of Ginsenoside Rb1 in the Intestinal Tract to the Enhancement of Ginsenoside Rb1 Exposure in Diabetic Rats after Oral Administration

Ginsenosides Regulate PXR/NF-κB Signaling and Attenuate Dextran Sulfate Sodium–Induced Colitis

Interactions between Phytochemicals from Traditional Chinese Medicines and Human Cytochrome P450 Enzymes

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