Hepatotoxicity in Rats Induced by Aqueous Extract of Polygoni Multiflori Radix, Root of Polygonum multiflorum Related to the Activity Inhibition of CYP1A2 or CYP2E1.

Deng-Ke Li,Jing Chen,Zhen-Xiao Sun,Zhen-Zhen Ge

doi:10.1155/2017/9456785

Abstract

The objective of this study is to investigate the relationship between the hepatotoxicity induced by Polygoni Multiflori Radix (PMR, root of Polygonum multiflorum Thunb., He Shou Wu) and the activity of CYP1A2 or CYP2E1 in the rat liver. Levels of rat serum transaminases ALT and AST were not altered but the activity of CYP1A2 or CYP2E1 in the rat liver was significantly inhibited after oral administration of aqueous extract of PMR under the experimental dosage. However, levels of ALT and AST were significantly increased and the activity of CYP1A2 or CYP2E1 was significantly decreased after injection of specific inhibitor for CYP1A2 or CYP2E1 combined with oral administration of aqueous extract of PMR, especially under the repeated treatment over interval times. Liver histopathological observation showed that a moderate liver injury occurred in rats receiving PMR treatment with the activity of CYP1A2 or CYP2E1 inhibited, but there was no significant liver damage in rats receiving PMR treatment or CYP inhibitor alone. These suggested that low level activity of CYP1A2 or CYP2E1 from genetic polymorphism among people might be one of the important reasons for the hepatotoxicity induced by PMR in clinical practice.

Highlights

Polygoni Multiflori Radix (PMR, root of Polygonum multiflorum Thunb., He Shou Wu) is a traditional Chinese medicine (TCM) that has been used in Chinese clinics for centuries
As PMR was proved to inhibit the activity of acetylcholinesterase (AChE) and 2,3,5,4󸀠-tetrahydroxystilbene-2-O-β-D-glucopyranoside (THSG) and emodin-8-O-β-D-glucoside (EG) as the main components in PMR were proved to decrease AChE activity and THSG increased the expression of protein phosphatase2A (PP-2A) and microtubule associated protein-2 (MAP-2) in the hippocampus of model rats, PMR was suggested to have the potential for antiaging such as Alzheimer’s disease treatment [4, 5]
According to a recent study on PMR related hepatotoxicity and genetic polymorphisms of CYP1A2 in clinical patients, the frequency of the CYP1A2∗1C allele is 46.5% in PMR induced drug induced liver injury (DILI) patients, which is significantly different from the frequency of 27.9% observed in healthy people, indicating that the increase of frequency of CYP1A2∗1C, which decreased the activity of CYP1A2, may be related to the acute liver injury induced by PMR [28]

Summary

Introduction

Polygoni Multiflori Radix (PMR, root of Polygonum multiflorum Thunb., He Shou Wu) is a traditional Chinese medicine (TCM) that has been used in Chinese clinics for centuries. RUCAM (Roussel Uclaf Causality Assessment Method) or later synonymously CIOMS (Council for International Organizations of Medical Sciences) was developed to cope with the shortcomings inherited in the causality assessment of drug induced liver injury (DILI). According to a recent study on PMR related hepatotoxicity and genetic polymorphisms of CYP1A2 in clinical patients, the frequency of the CYP1A2∗1C allele is 46.5% in PMR induced DILI patients, which is significantly different from the frequency of 27.9% observed in healthy people, indicating that the increase of frequency of CYP1A2∗1C, which decreased the activity of CYP1A2, may be related to the acute liver injury induced by PMR [28]. We found that enzymatic activity and mRNA expression of CYP1A2 and CYP2E1 in rat liver were significantly inhibited by the aqueous extract of PMR [29], suggesting that the combination of genetic polymorphisms and PMR may induce DILI in rats. This work aimed to investigate whether acute liver injury will occur when PMR is orally administrated to rats with liver CYP1A2 or CYP2E1 inhibited

Materials and Methods

Results

Discussions

Conclusions