Evaluation of the Hepatotoxicity of the Zhi-Zi-Hou-Po Decoction by Combining UPLC-Q-Exactive-MS-Based Metabolomics and HPLC-MS/MS-Based Geniposide Tissue Distribution.

Yunji Wang,Fang Feng

doi:10.3390/molecules24030511

Abstract

With traditional Chinese medicine (TCM) becoming widespread globally, its safety has increasingly become a concern, especially its hepatoxicity. For example, Gardenia jasminoides Ellis is a key ingredient in the Zhi-Zi-Hou-Po decoction (ZZHPD), which is a commonly-used clinically combined prescription of TCM that may induce hepatoxicity. However, the underlying toxicity mechanism of ZZHPD is not fully understood. In this study, a plasma metabolomics strategy was used to investigate the mechanism of ZZHPD-induced hepatotoxicity through profiling entire endogenous metabolites. Twenty-four Sprague-Dawley rats were randomly assigned into four groups, which were orally administered with 0.9% saline, as well as 2.7 g/kg/day, 8.1 g/kg/day, or 27 g/kg/day of ZZHPD for 30 consecutive days, respectively. Biochemical assay and metabolomics assay were used to detect serum and plasma samples, whilst histopathological assay was used for detecting liver tissues, and the geniposide distribution in tissues was simultaneously measured. The results showed that the concentration of 20 metabolites linked to amino acid, lipid, and bile acid metabolism had significant changes in the ZZHPD-treated rats. Moreover, toxic effects were aggravated with serum biochemical and histopathological examines in liver tissues as the dosage increased, which may be associated with the accumulation of geniposide in the liver as the dosage increased. Notably, our findings also demonstrated that the combined metabolomics strategy with tissue distribution had significant potential for elucidating the mechanistic complexity of the toxicity of TCM.

Highlights

The Zhi-Zi-Hou-Po decoction (ZZHPD) is a typical traditional Chinese medicine (TCM)prescription that was originally described in Shang-Han-Lun, and include Gardenia jasminoides Ellis (Zhi-Zi), Citrus aurantium L. (Zhi-Shi), and Magnolia officinalis cortex (Hou-Po)
The chronic toxicity of ZZHPD could be intuitively deduced from symptoms, such as hair pollution, hair loss and thinning, and loose stools in the 27 g/kg/day ZZHPD group
In the scatter plot of the orthogonal partial least squares discriminant analysis (OPLS-DA) (Figure 8), we found that samples from the 27 g/kg/day ZZHPD group and the control group were distributed in different areas, which indicated a differentiation in metabolic patterns between the control group and the 27 g/kg/day ZZHPD group

Summary

Introduction

The Zhi-Zi-Hou-Po decoction (ZZHPD) is a typical traditional Chinese medicine (TCM)prescription that was originally described in Shang-Han-Lun, and include Gardenia jasminoides Ellis (Zhi-Zi), Citrus aurantium L. (Zhi-Shi), and Magnolia officinalis cortex (Hou-Po). The Zhi-Zi-Hou-Po decoction (ZZHPD) is a typical traditional Chinese medicine (TCM). Prescription that was originally described in Shang-Han-Lun, and include Gardenia jasminoides Ellis (Zhi-Zi), Citrus aurantium L. Zhi-Zi, the main ingredient of the ZZHPD, has been reported to have significant antidepressant effects [3,4]. The dosage of Zhi-Zi is often increased to achieve the curative effect more rapidly. Concerns have been raised about the safety of herbal prescriptions [5], where an increasing number of reports suggest that Zhi-Zi induces liver toxicity [6,7]. There is no scientific evidence of the toxicity behind the Zhi-Shi [8,9] and

Methods

Results

Discussion

Conclusion