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-1β, IFN-γ, and MIP-2α 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.
Highlights
With a deep belief that traditional Chinese medicines (TCM) are safe because they are “natural,” TCM and related products are applied more and more widely in the world, especially in the fields of tonics, health products, and food (Luo et al, 2019)
Since diclofenac sodium itself is prone to liver damage, in order to reveal the objective authenticity of Xianling Gubao Capsule (XLGB)-induced liver injury, it is necessary to rule out the effects of other combination drugs, and only 36 cases of XLGB alone are included in the study
idiosyncratic drug-induced liver injury (IDILI) is determined by the interaction of environmental and host factors with the drug
Summary
With a deep belief that traditional Chinese medicines (TCM) are safe because they are “natural,” TCM and related products are applied more and more widely in the world, especially in the fields of tonics, health products, and food (Luo et al, 2019). In spite of predictable liver toxicity is often found in preclinical and clinical testing for drugs, it is extremely difficult to recognize or assess Chinese herbs-related to hepatotoxicity, especially idiosyncratic liver injury. Our previous research has indicated that mild inflammation might be one of the factors related to susceptibility of Chinese herbs (He shou wu in Chinese)-induced liver injury (Li et al, 2016; Li et al, 2017). We investigated the objectivity of XLGB-induced liver injury by analyzing clinical liver injury cases and simultaneously evaluated XLGB susceptibility on previously established animal models of mild immune stress. We employed a metabolomics strategy in order to explore the susceptibility related biomarkers of XLGB-induced liver toxicity from the perspective of metabolic reprogramming. The immune cytokines and differentially expressed biomarkers associated with the susceptibility factors of XLGB-induced liver injury were identified
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