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. 2018 Oct 12;19(10):3144.
doi: 10.3390/ijms19103144.

Effects of Panax Notoginseng Saponins on Esterases Responsible for Aspirin Hydrolysis In Vitro

Zongxi Sun  1 , Yali Wu  2 , Song Liu  3 , Shaonan Hu  4 , Bo Zhao  5 , Pengyue Li  6 , Shouying Du  7
Affiliations

Effects of Panax Notoginseng Saponins on Esterases Responsible for Aspirin Hydrolysis In Vitro

Zongxi Sun et al. Int J Mol Sci. .

Abstract

Herb⁻drug interactions strongly challenge the clinical combined application of herbs and drugs. Herbal products consist of complex pharmacological-active ingredients and perturb the activity of drug-metabolizing enzymes. Panax notoginseng saponins (PNS)-based drugs are often combined with aspirin in vascular disease treatment in China. PNS was found to exhibit inhibitory effects on aspirin hydrolysis using Caco-2 cell monolayers. In the present study, a total of 22 components of PNS were separated and identified by UPLC-MS/MS. Using highly selective probe substrate analysis, PNS exerted robust inhibitory potency on human carboxylesterase 2 (hCE2), while had a minor influence on hCE1, butyrylcholinesterase (BChE) and paraoxonase (PON). These effects were also verified through molecular docking analysis. PNS showed a concentration-dependent inhibitory effect on hydrolytic activity of aspirin in HepaRG cells. The protein level of hCE2 in HepaRG cells was suppressed after PNS treatment, while the level of BChE or PON1 in the extracellular matrix were elevated after PNS treatment. Insignificant effect was observed on the mRNA expression of the esterases. These findings are important to understand the underlying efficacy and safety of co-administration of PNS and aspirin in clinical practice.

Keywords: HepaRG cells; Panax notoginseng saponins; aspirin; herb–drug interactions.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The representative total ion current chromatogram of PNS in negative ESI modes. The corresponding compound names were given in Table 1 (varying from no. 1 to 19).
Figure 2
Figure 2
Inhibitory effects of PNS toward the esterases of hCE1, BChE, PON and hCE2 (A–D in order) with BMBT (2-(2-benzoyloxy-3-methoxyphenyl)benzothiazole), FD (Fluorescein diacetate), BuSCh (S-Butyrylthiocholine chloride) and PA (phenyl acetate) as a highly selective substrate of each esterase. BNPP, iso-OMPA, and EDTA are well-known inhibitors for hCE1 (hCE2), BChE, and PON, respectively. Data were presented as mean ± SD (n = 3).
Figure 3
Figure 3
Various concentrations of PNS were used to measure the half inhibition concentration toward hCE2. Each point represents the mean of three independent experiments.
Figure 4
Figure 4
Inhibitory kinetics of PNS toward hCE2 using Lineweaver-Burk plots (A) and Dixon plots (B). Data were presented as mean ± SD (n = 3).
Figure 5
Figure 5
Molecular docking mode and interactions between hCE2 (shown in cartoon representation and colored structure) and notoginsenoside R1, ginsenoside Rg1, Re, Rb1, and Rd (indicated by arrow), respectively. Three-dimensional illustrations show the interactions of hCE2 with notoginsenoside R1 (A), ginsenoside Rg1 (C), Re (E), Rb1 (G), and Rd (I). Two-dimensional diagrams display interactions of notoginsenoside R1 (B), ginsenoside Rg1 (D), Re (F), Rb1 (H), and Rd (J) in the active sites of hCE2.
Figure 5
Figure 5
Molecular docking mode and interactions between hCE2 (shown in cartoon representation and colored structure) and notoginsenoside R1, ginsenoside Rg1, Re, Rb1, and Rd (indicated by arrow), respectively. Three-dimensional illustrations show the interactions of hCE2 with notoginsenoside R1 (A), ginsenoside Rg1 (C), Re (E), Rb1 (G), and Rd (I). Two-dimensional diagrams display interactions of notoginsenoside R1 (B), ginsenoside Rg1 (D), Re (F), Rb1 (H), and Rd (J) in the active sites of hCE2.
Figure 6
Figure 6
Cytotoxicity tests of PNS on HepaRG cells. Data were presented as mean ± SD (n = 5). ** and *** denoted result significantly different from that of the control group (p < 0.01 and p < 0.001, respectively).
Figure 7
Figure 7
Hydrolysis of aspirin (ASA) in HepaRG cell homogenates treated with PNS. HepaRG cells homogenates were prepared and then diluted with 50 mM HEPES buffer (pH 7.4). Hydrolysis of ASA (1.8 µg/mL) in cell homogenates was conducted in the presence/absence of PNS. No significance (ns) was detected between BNPP (68 µg/mL) and PNS (150 µg/mL) treated group. Data were presented as mean ± SD (n = 3). *, and ** denoted results significantly different compared with the control group (p < 0.05, p < 0.01, respectively).
Figure 8
Figure 8
Effects on human carboxylesterase 1 (hCE1) (A), hCE2 (B), BChE (C,D), and PON1 (E,F) protein level after PNS treatment. Cells were incubated with PNS for up to 24 h. After the removal of PNS, cell lysates were prepared for ELISA analysis. Data were presented as mean ± SD (n = 3). * and ** denote results significantly different from those of the control group (p < 0.05, p < 0.01, respectively).
Figure 9
Figure 9
Effects on mRNA expression of human carboxylesterase 1 (hCE1) (A), hCE2 (B), BChE (C), and PON1 (D) with PNS treatment. Cells were incubated with PNS for up to 24 h. After the removal of PNS, total mRNA was prepared for qRT-PCR. Data were presented as mean ± SD (n = 3).
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