Pharmacokinetic characteristics of emodin in polygoni Multiflori Radix Praeparata

Polygoni Multiflori Radix Praeparata (制何首乌, Zhiheshouwu), a tonics in Wudang Taoist medicine from Polygonum multiflorum (Thunb.), or Reynoutria multiflora (Thunb.) Moldenke in “World Flora Online” (www.worldfloraonline.org) (family: Polygonaceae), is known as steamed Polygoni Multiflori Radix (何首乌, Heshouwu) with black bean juice in China (Pharmacopeia, 2020). According to the philosophy of traditional Chinese medicine, Zhiheshouwu tonifies the liver and kidney, replenishes essence and blood, blackens beard and hair, strengthens sinew and bone (Pharmacopeia, 2020). The studies showed that Zhiheshouwu exerts actions such as anti-oxidation (Lin et al., 2015a), anti-cancer (Choi et al., 2007; Sun et al., 2015), anti-aging (Chen et al., 2016), anti-ischemic brain injury (Sun et al., 2019; Wang et al., 2009), osteoblast protection (Fan et al., 2018), neuroprotection (He et al., 2015), hepatoprotection (Ruan et al., 2019) and enhancing learning and memory ability (Wang et al., 2011, 2019). There are more than 175 compounds in Zhiheshouwu including stilbenes (e.g., 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside, polygonumoside E and 2,3,5,40-tetrahydroxystilbene-2-O-β-D-(2″-omonogalloylesters)-glucopyranoside, etc), anthraquinones (e.g., emodin, aloe-emodin, chrysophanol, physcion, rhein, citreorosein, emodin-8-O-β-D-glucopyranoside, physcion-8-O-β-D-glucopyranoside, chrysophanol-8-O-β-D-glucopyranoside, polygonumnolide C1, and danthron, etc.), flavonoids (e.g., rutin, tricin, and quercetin, etc.), phospholipids (e.g., phosphatidyl ethanolamine, copaene, and eicosane, etc.) and others (e.g., gallic acid, β-sitosterol, and indole-3-(L-α-amino-α-hydroxypropionicacid) methyl ester, etc.) (Chen et al., 2000; Li et al., 2017; Lin et al., 2015a; Liu et al., 2009; Rao et al., 2009; Teka et al., 2021; Yang et al., 2016; Zhao et al., 2016).

Our previous studies showed that 400 μg/mL of Zhiheshouwu extract (HSWE) induced apoptosis in liver cancer cells via inhibition of sterol regulatory element binding protein 1 (SREBP1), a lipid metabolism-associated protein (Li et al., 2018). We also found that emodin (EM), the main active anthraquinone (Yang et al., 2018), blocked SREBP1 at 100 μM in liver cancer cells (Yang, N. et al., 2019). Of note, interestingly, 400 μg/mL HSWE had the same inhibitory effects as 100 μM EM alone. Since the concentration of EM in HSWE was about 0.1% (g/g) (Li et al., 2018), which means the molar concentration of EM (molecular weight 270.24) in the HSWE was about 1.48 μM, far less than that of EM alone (100 μM). This indicates that other components in HSWE may also inhibit SREBP1, and/or exert drug-interactions with EM. Actually, our previous study did show that other components, rhein (RH), aloe-emodin (AE) and physcion (PH) inhibited the growth of liver cancer cells by blocking SREBP1, the IC50 values were 98.9, 277.7 and 348.8 μM, respectively (Yang et al., 2018). Concerning drug-interactions between the anthraquinones, Li et al. reported that AE, RH, CH and PH decreased blood concentration in rats with cerebral ischemia (Li et al., 2019). However, it is still unknown if other anthraquinones enhance pharmacokinetics (PK) of EM in HSWE in rats.

As there are more than 20 kinds of anthraquinones in HSWE of which have a complex interaction network in PK (Wang, D. et al., 2021), in this study, we postulated that other anthraquinones might enhance the effects of EM by improving PK of EM in HSWE. We firstly compared the PK parameters of EM alone with that of EM in HSWE, and subsequently investigated the PK parameters of EM alone and that of in combination with the other common anthraquinones, physcion (PH), chrysophanol (CH), rhein (RH), aloe-emodin (AE), emodin-8-O-β-D-glycoside (EMG), physcion-1-O-β-D-glycoside (PHG) and chrysophanol-8-O-β-D-glycoside (CHG), aiming to explore if the changed PK parameter of EM in HSWE was associated with these anthraquinones. In addition, we also studied how HSWE and its anthraquinones, PH, CH, RH, AE, EMG, PHG and CHG affected the concentration of EM in intestinal issues. This study may firstly shed light on the PK characteristics of EM in HSWE.

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