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

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.

Effects of medicine food Fructus Gardeniae on liver and kidney functions after oral administration to rats for 12 weeks

“…Some research has also evaluated the hepatotoxicity of decocted Zhi‐Zi‐Hou‐Po. In this regard, preliminary results have confirmed that the oral administration of 8.1 and 27 g kg −1 day −1 Zhi‐Zi‐Hou‐Po may lead to liver injury 30 days later, as shown by serum biochemical indexes and pathological examination (Wang & Feng, 2019). The safe dose of FG recommended by the Chinese Pharmacopoeia is 6–10 g/day.…”

The Effects of Different Varieties of Aurantii Fructus Immaturus on the Potential Toxicity of Zhi-Zi-Hou-Po Decoction Based on Spectrum-Toxicity Correlation Analysis

“…It is well known that the treatment of depression is a process that requires long-term medication. The possibility of hepatotoxicity after the repeated administration of ZZHPD has been confirmed by our laboratory, which is mainly related to gardenoside [9]. ZS is an important herbal medicine in ZZHPD, which has a synergistic effect, along with two other herbs.…”

Integrated Network Pharmacology Analysis and Experimental Validation to Investigate the Mechanism of Zhi-Zi-Hou-Po Decoction in Depression

“…Many studies have shown that TCM has broad prospects in the prevention and treatment of major depression disorder (Sun et al, 2018;Ye et al, 2019). Zhi-Zi-Hou-Po Decoction (ZZHPD), being composed of the stem, branch, and root barks of Magnolia officinalis Rehder & E.H.Wilson (Hou-Po, HP), the ripe fruit of Gardenia jasminoides J.Ellis (Zhi-Zi, ZZ), and the young fruit of Citrus × aurantium L. (Zhi-Shi, ZS), is a classic prescription for relieving restlessness and removing fullness in the TCM masterpiece "Treatise on Febrile and Miscellaneous Diseases," compiled by Zhang Zhongjing (AD 150-219) (Wang and Feng, 2019;Zhang and Feng, 2020). ZZHPD has often been utilized in clinical practice to treat mental disorders, especially major depression disorder (Luo and Feng, 2016).…”