Network Pharmacology-Based Prediction and Verification of Qingluo Tongbi Formula to Reduce Liver Toxicity of Tripterygium wilfordii via UGT2B7 in Endoplasmic Reticulum

Abstract

The hepatotoxicity of Tripterygium wilfordii Hook. f. (TWHF) limits its clinic utilization. Qingluo Tongbi formula (QTF) was formulated based on a basic Chinese medicine theory. Previous studies have confirmed the safety and efficacy of QTF in treating rheumatoid arthritis. Therefore, we considered that TWHF could be detoxified based on its reasonable compatibility with QTF. We investigated the detoxicity mechanism of QTF in reducing the liver toxicity of TWHF. Material/Methods:We used network pharmacology to determine the relevant metabolism targets of TWHF, focusing on the phase II metabolic enzymes uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1), UGT1A6, and UGT2B7. Based on the molecular mechanisms of these predictions and the results of the network analysis, we designed experiments to verify our hypothesis in vivo. We used western blotting, real-time quantitative polymerase chain reaction (RT-qPCR), double immunofluorescence, and laser confocal microscopy to detect the expression of UGTs. Finally, we used transmission electron microscopy to observe the endoplasmic reticulum structure. Results:The results confirmed that QTF reversed the TWHF-induced reduction of UGT content in liver microsomes, upregulated UGT1A1 and UGT1A6 but not UGT2B7 in the liver tissue. UGT2B7 expression in the liver and liver microsomes was inconsistent. QTF upregulated the expression of UGT2B7 in the endoplasmic reticulum, and QTF upregulated UGT2B7 expression levels in the endoplasmic reticulum compared with TWHF, which reduced liver toxicity. Structural changes were observed in the endoplasmic reticulum. Conclusions:The Chinese traditional medicine compound QTF can achieve the effect of detoxification by upregulating the expression of UGT2B7 in the endoplasmic reticulum.

Application of the adverse outcome pathway concept for investigating developmental neurotoxicity potential of Chinese herbal medicines by using human neural progenitor cells in vitro

“…LGT is classified as a toxic herb in the Chinese Pharmacopoeia (Chinese Pharmacopoeia Commission 2020), as it is known to be toxic to humans, rats, dogs, pigs, and insects, but non-toxic to sheep, rabbits, cats, and fish (Chinese Pharmacopoeia Commission 2020; Zhang et al 1984 ). Toxicity was reported for the gastrointestinal system (Liu et al 2018a ), the central nervous system (hypothalamus, midbrain, medulla, cerebellum, and spinal cord; Wang et al 2016 ), and the cardiovascular system (Wang et al 2020 ), while bleeding and necrosis of the liver were also observed (Li et al 2020b ). LGT is mainly used as a treatment for leprosy, rheumatoid arthritis, tuberculosis, and other chronic lung disorders (Chen 2001 ; Wang et al 2018 ; Song et al 2020a ).…”

Potential Molecular Mechanisms and Drugs for Aconitine-Induced Cardiotoxicity in Zebrafish through RNA Sequencing and Bioinformatics Analysis

“…The innovative, well-designed, and systematic safety studies should be carried out step by step to achieve a comprehensive exploration of morphology-molecular mechanisms-gene targets in drug toxicity. The continuous advancement of high-throughput sequencing, bioinformatics analysis, and network pharmacology [51,52] provide new research ideas for pharmacology and toxicology.…”

Investigation of the mechanism of nephrotoxicity of nux‐vomica by PTGS2/CYP2C9‐mediated arachidonic acid pathway and Jian Pi Tong Luo compound's protective effect

“…Similarly, the Qing Luo Tong Bi compound has demonstrated the ability to regulate UGT2B7 activity in the endoplasmic reticulum, thereby reducing the liver toxicity associated with Tripterygium wilfordii Hook. f. (M. Li, Wang, et al, 2020). The Tiao Wei Cheng Qi Tang compound has been observed to mitigate the intestinal absorption of rhein, consequently alleviating the toxicity associated with Rheum L. in vitro (Peng et al, 2018).…”