Hepatic Uptake Mechanism of Ophiopogonin D Mediated by Organic Anion Transporting Polypeptides

Zhang, Wen; Xiong, Xiaomin; Chen, Lin; Liu, Mingyi; Xiong, Yan; Zhang, Hong; Huang, Shibo; Xia, Chunhua

doi:10.1007/s13318-016-0384-8

Cited by 10 publications

(11 citation statements)

References 25 publications

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“…Such features determine the pharmacologic activities of the original forms of these compounds, which are instead prone to be metabolized and hydrolyzed by the gut microbiota, and which function as secondary glycosides or aglycons (49,50). It has been reported that OATP1B1, a member of the organic anion transporting polypeptide (OATP) family, mediates hepatic uptake of OP-D (51). However, our pharmacokinetic study revealed that clearance of OP-D in the liver after i.v.…”

Section: Discussionmentioning

confidence: 78%

Ophiopogonin D alleviates high‐fat diet‐induced metabolic syndrome and changes the structure of gut microbiota in mice

Chen

Liu

et al. 2018

FASEB j.

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Gut dysbiosis is believed to play a critical role in the pathogenesis of metabolic diseases, including obesity. Ophiopogonin D (OP-D), a steroidal glycoside and an active component extracted from the root of the plant Ophiopogon japonicus (also known as radix ophiopogonis), can regulate multiple physiologic processes. Here we show that OP-D administration reduces body weight, hyperglycemia, hyperlipidemia, and insulin resistance in male mice fed a high-fat diet (HFD). Pyrosequencing of the V4 regions of 16S rRNA genes in mouse feces revealed a deviation of the gut microbiota in response to OP-D treatment. In particular, the decreased Firmicutes-to- Bacteroidetes ratios and endotoxin-bearing Proteobacteria levels indicated that OP-D reversed HFD-induced gut dysbiosis. More importantly, the effects of OP-D on modulation of obesity and microbiota were transferable via horizontal feces transfer from OP-D-treated mice to HFD-fed mice. Taken together, our results suggest that OP-D may be used as a prebiotic agent to treat obesity-associated gut dysbiosis and metabolic syndrome.-Chen, S., Li, X., Liu, L., Liu, C., Han, X. Ophiopogonin D alleviates high-fat diet-induced metabolic syndrome and changes the structure of gut microbiota in mice.

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Section: Discussionmentioning

confidence: 78%

Ophiopogonin D alleviates high‐fat diet‐induced metabolic syndrome and changes the structure of gut microbiota in mice

Chen

Liu

et al. 2018

FASEB j.

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“…Our previous study demonstrated that the plasma concentrations of OPD in rats administered with SMI are higher than those administered with the same dose of OPD, and the ratio of the plasma concentration to the liver tissue concentration of OPD in SMI group was about 5–7 times greater than those in OPD group ( Xia et al, 2008a ). We also found that OPD can be taken by rat primary hepatocytes, and transported by OATP1B1-expressing HEK293 cells ( Zhang et al, 2017 ). These results indicated potential interactions between other components and OPD in SMI treated group.…”

Section: Introductionmentioning

confidence: 80%

“…After incubating for 10 min at 37°C, the cell suspensions were transferred into 1.5-mL plastic tubes and centrifuged for 4 min at a speed of 600 rpm, and then the supernatants were aspirated to terminate the uptake. Subsequently, the cell pellets were washed thrice with PBS at 4°C as described in our previous study ( Zhang et al, 2017 ). Cells were then lysed with 1 mL of sterilized ultrapure water by repeated freezing and thawing.…”

Section: Methodsmentioning

confidence: 99%

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Ginsenoside Rb1 and Rd Remarkably Inhibited the Hepatic Uptake of Ophiopogonin D in Shenmai Injection Mediated by OATPs/oatps

et al. 2018

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Shenmai injection (SMI) is derived from traditional Chinese herbal prescription Shendong yin and widely used for treating cardiovascular diseases. Ophiopogonin D (OPD) is one of the main active components of SMI. The hepatic uptake of OPD is mediated by organic anion-transporting polypeptides (OATPs/oatps) and inhibited by some other components in SMI. This study aimed to identify the active components of SMI responsible for the inhibitory effects on hepatic uptake of OPD in rats and explore the compatibility mechanisms of complex components in SMI based on OATPs/oatps. The known effective fractions, the known components in Shenmai Formula, and the fractions obtained from SMI by HPLC gradual-separation technology were individually/combinedly tested for their effects on OPD uptake in rat primary hepatocytes and recombinant OATP1B1/OATP1B3-expressing HEK293T cells. The results indicated that the OPD uptake was inhibited by panaxadiol-type ginsenosides (ginsenoside Rb1 and Rd), but slightly influenced by panaxatriol-type ginsenosides in rat primary hepatocytes and recombinant cells. The fractions of SMI-3-1 (0–11 min) and SMI-3-3 (15–20 min) obtained by HPLC gradual-separation technology were proved to be the major effective fractions that influenced the OPD uptake, and subsequently identified as ginsenoside Rb1 and Rd, respectively. The plasma concentrations of OPD in rats given OPD+ginsenoside Rb1+ginsenoside Rd were higher compared to rats given OPD alone at the same dose. In conclusion, ginsenoside Rb1 and Rd are the major effective components in SMI that remarkably inhibited the hepatic OPD uptake mediated by OATPs/oatps. The interaction of complex components by OATPs/oatps may be one of the important compatibility mechanisms in SMI.

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“…In another article we submitted, molecular modeling was adopted and screen out a protein called Q9NPD5 which can interact with both OPD and OPD'. This protein belongs to organic anion transporters (OATP) family and it was closely related to cholic acid metabolism [28], existing studies have con rmed that the down-regulation of OATP1A2 and OATP1B3 in particular leads to abnormal fetal bile acid metabolism between maternal and fetal fetuses [29]. This may explain from another perspective how OPD and OPD' induce hemolysis.…”

Section: Metabolic Changes Induced By Opd and Opd' In Vivomentioning

confidence: 99%

Global Metabolomic and Lipidomic Analysis Reveals the Potential Mechanisms of Hemolysis Effect of Ophiopogonin D and Ophiopogonin D’ in vivo

Jiang²,

Huang

et al. 2020

Preprint

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Background OPD and OPD’ are the two main active monomers of Ophiopogon japonicus in Shenmai injection, being isomers of each other with the same chemical formula and similar chemical structure. According to common sense, they are supposed to have similar pharmacological activities, but the actual situation is exactly the opposite. The difference of distinct hemolytic behavior between OPD and OPD’ in vivo and in vitro was discovered and reported by our group for the first time. In the hemolysis experiment in vitro, only OPD’ showed hemolysis reaction, while in vivo, both OPD and OPD’ revealed hemolysis reaction. The primary cause of hemolysis in vitro has been confirmed to be related to the difference between physical and chemical properties of OPD and OPD’, but the mechanism of hemolysis in vivo is still unclear, especially the existing research are still difficult to explain why OPD shows the inconsistent hemolysis behavior in vivo and in vitro. However, the detection of hemolysis of OPD and OPD’ in vivo is of great practical significance in response to the increase of adverse events of Shenmai injection. Methods Aiming at the phenomenon of hemolysis in vivo, this paper adopted untargeted metabolomics and lipidomics technology to preliminarily explore the changes of plasma metabolites and lipids of OPD and OPD’ in vivo during the occurrence of hemolysis. Metabolomics and lipidomics analysis was performed on ultra-high performance liquid chromatography (UPLC) system tandem with different mass spectrometer and different columns respectively. Multivariate statistical approaches such as principal component analysis (PCA) and orthogonal partial least square-discriminant analysis (OPLS-DA) were applied to screen the differential metabolites and lipids. Results Both OPD and OPD’ groups experienced hemolysis, Changes in endogenous differential metabolites and differential lipids, enrichment of differential metabolic pathways, and correlation analysis of differential metabolites and lipids all indicated that the causes of hemolysis by OPD and OPD’ were closely related to the interference of phospholipid metabolism. Conclusions This study provided a comprehensive description of metabolomics and lipidomic changes between OPD and OPD’ treated rats, which also provided scientific guidance for the subsequent mechanism research, and the underlying mechanism require further research.

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Hepatic Uptake Mechanism of Ophiopogonin D Mediated by Organic Anion Transporting Polypeptides

Abstract: Overall, this study indicates OATP1B1 in human and oatp1b2 in rats might participate in the hepatic uptake of OPD.

Cited by 10 publications

References 25 publications

Ophiopogonin D alleviates high‐fat diet‐induced metabolic syndrome and changes the structure of gut microbiota in mice

Ophiopogonin D alleviates high‐fat diet‐induced metabolic syndrome and changes the structure of gut microbiota in mice

Ginsenoside Rb1 and Rd Remarkably Inhibited the Hepatic Uptake of Ophiopogonin D in Shenmai Injection Mediated by OATPs/oatps

Global Metabolomic and Lipidomic Analysis Reveals the Potential Mechanisms of Hemolysis Effect of Ophiopogonin D and Ophiopogonin D’ in vivo

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