Screening for Susceptibility-Related Factors and Biomarkers of Xianling Gubao Capsule-Induced Liver Injury

Abstract

Although increasing reports from the literature on herbal-related hepatotoxicity, the identification of susceptibility-related factors and biomarkers remains challenging due to idiosyncratic drug-induced liver injury (IDILI). As a well-known Chinese medicine prescription, Xianling Gubao Capsule (XLGB) has attracted great attention due to reports of potential liver toxicity. But the mechanism behind it is difficult to determine. In this paper, we found that XLGB-induced liver injury belongs to IDILI through the analysis of clinical liver injury cases. In toxicological experiment assessment, co-exposure to XLGB and non-toxic dose of lipopolysaccharide (LPS) could cause evident liver injury as manifested by significantly increased plasma alanine aminotransferase activity and obvious liver histological damage. However, it failed to induce observable liver injury in normal rats, suggesting that mild immune stress may be a susceptibility factor for XLGB-induced idiosyncratic liver injury. Furthermore, plasma cytokines were determined and 15 cytokines (such as IL-1b, IFN-g, and MIP-2a etc) were acquired by receiver operating characteristic (ROC) curves analysis. The expression of these 15 cytokines in LPS group was significantly up-regulated in contrast to the normal group. Meanwhile, the metabolomics profile showed that mild immune stress caused metabolic reprogramming, including sphingolipid metabolism, phenylalanine metabolism, and glycerophospholipid metabolism. 8 potential biomarkers (such as sphinganine, glycerophosphoethanolamine, and phenylalanine etc.) were identified by correlation analysis. Therefore, these results suggested that intracellular metabolism and immune changes induced by mild immune stress may be important susceptibility mechanisms for XLGB IDILI.

Identification of naturally occurring inhibitors in Xian-Ling-Gu-Bao capsule against the glucuronidation of estrogens

“…Therefore, CFDA has also warned of the risks of liver damage from XLGB in 2016 and turned this drug from over-the-counter treatment to prescription. Furthermore, when lipopolysaccharide (LPS) and XLGB were co-administrated to OVX rats, marked hepatotoxicity was observed ( Wu et al, 2019 ; Li et al, 2020 ). Also, mild immune stress, disrupted lipid metabolism, extensive liver necrosis and inflammatory infiltration, apoptosis, and expression of oxidative stress-related proteins may be associated with XLGB-induced hepatotoxicity in humans ( Wu et al, 2019 ; Li et al, 2020 ).…”

“…Furthermore, when lipopolysaccharide (LPS) and XLGB were co-administrated to OVX rats, marked hepatotoxicity was observed ( Wu et al, 2019 ; Li et al, 2020 ). Also, mild immune stress, disrupted lipid metabolism, extensive liver necrosis and inflammatory infiltration, apoptosis, and expression of oxidative stress-related proteins may be associated with XLGB-induced hepatotoxicity in humans ( Wu et al, 2019 ; Li et al, 2020 ). Meanwhile, eight endogenous components including sphinganine, glycerophosphoethanolamine, and phenylalanine were identified as the potential biomarkers for XLGB-induced liver injury ( Li et al, 2020 ).…”

Plasma Metabolomics Identifies the Dysregulated Metabolic Profile of Primary Immune Thrombocytopenia (ITP) Based on GC-MS

“…Higher serum phenylalanine levels related to immune activation were detectable in patients with Alzheimer’s disease, in the pathogenesis of which immune activation and inflammation represented critical mechanisms ( Wissmann et al, 2013 ). Li et al suggested that mild immune stress caused metabolic reprogramming including phenylalanine metabolism ( Li C.Y. et al, 2020 ), implicating a potential relationship between immunomodulation and phenylalanine related metabolic pathways.…”

Investigation of Gynura segetum root extract (GSrE) induced hepatotoxicity based on metabolomic signatures and microbial community profiling in rats

“…In fecal metabolomics, the level of phenylalanine increased after low-dose administration both on day 10 and day 21. Phenylalanine was identified as a potential biomarker of drug-induced hepatotoxicity with metabolomics analysis (Li et al, 2020a ; Tu et al, 2021 ).…”