Abstract
The liver injury induced by Polygonum multiflorum (PM) used for clinical treatment has recently received widespread attention. This study aimed to determine the hepatotoxicity of PM through pharmacokinetics studies. The extract of PM was separated to isolate the anthraquinone fraction, the tannin and polysaccharide fraction, the hydroxystilbene fraction, and the combined anthraquinone fraction. A rapid LC-MS/MS method was developed and validated to simultaneously analyze 2,3,5,4′-tetrahydroxystilbene-2-O-β-glucoside (TSG), emodin-8-O-β-D-glucopyranoside (EDG), and emodin in rat plasma, and was applied to the pharmacokinetics (PK) studies. The hepatotoxicity of different extracted parts of PM was evaluated through the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBil), direct bilirubin (DBil), and indirect bilirubin (IBil) in rat serum. The results showed that liver injury occurred in all the treated groups and that the hepatotoxicity performance of the total extract was different from other groups. The pharmacokinetic studies showed that the Cmax, Tmax, AUC, t1/2, and MRT of the major compounds of different extracted parts were significantly different in rat plasma at same dosage. Emodin-O-hex-sulfate, tetrahydroxystilbene-O-(galloyl)-hex, emodin (original and generated through EDG deglycosylation), and other free anthraquinones might be responsible for the hepatotoxicity of PM in vivo. PM extracts produced inhibitory effects on drug metabolic enzymes, include CYP3A4, CYP2C19, CYP2E1, UGT1A1, etc. And these effects may be related to its hepatotoxicity and pharmacokinetic behavior different. This information on hepatotoxicity and the pharmacokinetic comparison may be useful to understand the toxicological effects of PM.
Highlights
Polygonum multiflorum (PM) is the roots of polygonaceae plants radix Polygoni multiflori
Changes of Biochemical Indexes Related to Hepatocyte Injury ALT, AST, and alkaline phosphatase (ALP) are biochemical indexes that could reflect the level of hepatocyte injury
The serum AST and ALT levels of HDP group were most obviously increased (Figure 3A). These results indicated the occurrence of liver injury in these four groups of rats
Summary
Polygonum multiflorum (PM) is the roots of polygonaceae plants radix Polygoni multiflori. The ingredients in PM were separated by type by using a process described in our previous studies (Lin L.F. et al, 2017), which produced the free anthraquinone fraction (the content mainly including free anthraquinone), tannins and polysaccharide fraction (the content mainly including tannins and polysaccharide), hydroxystilbene fraction (mainly composed of polyhydroxystilbene, such as 2,3,5,4’-tetrahydroxystilbene-2O-β-glucoside, TSG), and the combined anthraquinone fraction (mainly composed of combined anthraquinones, such as emodin8-O-β-D-glucopyranoside, EDG). The hepatotoxic of these extracts was investigated to further validate the above results in vivo The pharmacokinetics of these extracts were investigated through a rapid, specific, and sensitive LC-MS/MS that was developed and validated for the simultaneous determination of TSG, EDG, and emodin in rat plasma after the oral administration of the different extracted fractions of PM. A deeper understanding of the hepatotoxic effects of PM is obtained through the comparison of the pharmacokinetic parameters of the main components (TSG, EDG, and emodin) of different extractions of PM
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