Hepatotoxicity and Related Components of Polygoni Multiflori Radix Based on Cytochrome Oxidase CYP2D6

doi:10.19803/j.1672-8629.2021.03.04

Abstract

Abstract: Objective To study the effects of Polygoni Multiflori Radix and its main components on the mRNA expression of CYP2D6 in L02 human liver cells and the effects of CYP2D6 inhibition on Polygoni Multiflori Radix and its main components induced hepatocyte toxicity. Methods The mRNA expression of CYP2D6 was determined by RT-XqPCR in L02 cells treated with Polygoni Multiflori Radix (PMR) or its main components. Quinidine (CYP2D6 inhibitor) was used to explore the cytotoxic effect of PMR on L02 cells with low CYP2D6 activity. Then, L02-shCYP2D6 cell line was constructed by RNA interference and used to investigate the main hepatotoxic components of PMR related to CYP2D6. Finally, the major CYP450 enzymes that affected the metabolism of possible hepatotoxic components were determined by the substrate metabolic clearance rate in human liver microsomes after different CYP450 enzyme specific inhibitors were added. Results PMR and aloe-emodin (AE), rather than emodin (EM), inhibited the mRNA expression of CYP2D6 significantly (P<0.01), while 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) activated mRNA expression of CYP2D6 at a high concentration (P<0.01). PMR exerted more cytotoxic effect in L02 cells at a high concentration (P<0.01) when combined with quinidine than used alone. Hepatotoxicity was increased significantly when PMR was combined with quinidine at various concentrations (P<0.01). PMR, EM and AE increased hepatotoxicity significantly in L02-shCYP2D6 cells within the experimental concentration range (P<0.01), but TSG increased hepatotoxicity only at high concentrations (P<0.01). CYP2D6 was determined as an important metabolic enzyme for EM and AE in human liver microsomes. Conclusion PMR can inhibit the expression of CYP2D6 in hepatocytes. The low activity or low expression of CYP2D6 aggravates the hepatotoxicity of PMR and its main toxic components are EM and AE.

Key words: Polygoni Multiflori Radix, metabolic idiosyncratic hepatotoxicity, CYP2D6, human liver parenchymal L02 cells, emodin, aloe-emodin, RNA interference

CLC Number:

R994.11

WANG Chengyu, LI Dengke, QUAN Zhengyang, HU Yinghuan, SUN Zhenxiao. Hepatotoxicity and Related Components of Polygoni Multiflori Radix Based on Cytochrome Oxidase CYP2D6[J]. Chinese Journal of Pharmacovigilance, 2021, 18(3): 220-227.

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