Rhus chinensis Mill. fruits alleviate liver injury induced by isoniazid and rifampicin through regulating oxidative stress, apoptosis, and bile acid transport
Introduction
The liver is the major organ of human metabolism, with functions of bile secretion and detoxification (Apte and Krishnamurthy, 2020). Many adverse factors, including alcohol, high-fat diet and drugs can cause liver diseases (e.g., hepatitis, cirrhosis, and liver cancer). With the increasing variety and quantity of drugs on the market, the incidence of drug-induced liver injury (DILI) is also proliferating. Clinically, DILI is responsible for approximately 1/10 of the cases of adverse drug reactions (ADRs) (Pan et al., 2019). Tuberculosis (TB) is the leading cause of infectious disease deaths worldwide, mainly caused by Mycobacterium tuberculosis infection, causing 9.6 million new cases and 1.5 million deaths annually (Manjelievskaia et al., 2016; Raviglione and Sulis, 2016). Isoniazid (INH) and rifampicin (RIF), as clinical first-line anti-TB medications, used in combination have the potential to significantly inhibit bacterial infection and reduce resistance (He et al., 2017). However, long-term use of INH and RIF can cause serious ADRs and impede the course of TB treatment (Li et al., 2017; Sharma and Mohan, 2017). Therefore, seeking auxiliary or alternative therapies with high safety and less side effects to alleviate anti-TB drug-induced liver injury is necessarily urgent.
Studies have exhibited that hepatotoxicity caused by anti-TB drugs (INH and RIF) is mainly caused by toxic substances produced by cytochrome P450 (CYP450) enzyme family (Guo et al., 2011; Wang et al., 2018). CYP2E1 is a critical drug metabolism cytochrome enzyme, which can induce INH metabolism to generate hydrazine (Yue et al., 2004). RIF is an effective inducer of CYP2E1, which may aggravate INH-induced hepatotoxicity by accelerating the production of hydrazine (YuePeng, 2009). Shih et al. studied that Kaempferol could reduce liver injury caused by INH/RIF via inhibiting the activity of CYP2E1 (Shih et al., 2013). Our previous research also found that the extract of the fruits can ameliorate acetaminophen (APAP)-caused liver damage through decreasing the CYP2E1 expression (Sun et al., 2021a, Sun et al., 2021b). Hydrazine is converted into non-toxic substances by consuming GSH in the body (Chowdhury et al., 2006), which catalyzes the generation of reactive oxygen species (ROS) in this process. When prolonged use of INH and RIF, hydrazine accumulates in the liver, consuming a large amount of GSH and aggravating the oxidative stress response of the body. Meanwhile, hydrazine and acetylhydrazine is responsible for the covalent binding and toxicity of INH (Metushi et al., 2012). Oxidative stress can stimulate Kupffer cells to produce pro-inflammatory cytokines (TNF-α IL-6 and IL-1β), and induce apoptosis of hepatocytes (Sun et al., 2021a, Sun et al., 2021b). Studies have shown that DILI caused by INH/RIF can cause bile acid imexcretion (Metushi et al., 2016; Zhou et al., 2016). Key transporters of bile acids (BSEP and Mrp2) play an important role in bile acid export from liver to bile duct (T. Ren et al., 2021). He et al. found that Pyrrolidine dithiocarbamate can reduce INH/RIF-induced liver injury by up-regulating the expression of BSEP protein (He et al., 2020).
Rhus chinensis Mill., a member of the genus Rhus, mainly distributed in temperate, subtropical, and tropical regions (Sun et al., 2021a, Sun et al., 2021b). Rhus chinensis is a deciduous tree or shrub with orange-red fruits at maturity, low water content but high in crude fiber (Devi and Singh, 2018). Accordance with folk medicine records, the fruits of this plant are traditional used as herbs to cure jaundice and hepatitis (Djakpo and Yao, 2010). A review also exhibited that Rhus chinensis Mill. has rich pharmacological activities (Y. Ren et al., 2021). Zhang et al. also reviewed the phytochemical characteristics and biological activities of Rhus chinensis Mill. fruits (J-K. Zhang et al., 2022). Apart from that, our previous studies have found that the ethanol extract of the fruits had good protective effects against liver related diseases such as fatty liver and fibrosis (Zhou et al., 2020; Wu et al., 2019, 2020). Thus, we speculate that the extract of this fruits also has a good preventive effect to alleviate INH/RIF-induced liver injury, which has not been investigated and thereby needing to be proved. Thus, the purpose of this study was to explore the protective effect of the extract on liver injury induced by INH/RIF and to reveal its potential protective mechanism. Rhus chinensis Mill. fruits, as a traditional herb, can provide some and scientific knowledges for exploiting these functional foods to reduce the side effects of anti-TB drugs.
Section snippets
Chemical and reagents
INH (CAS:54-85-3) and RIF (CAS:13,292-46-1) were purchased from Adamas-beta (Shanghai, China). Acetonitrile and methanol, belongs to HPLC/MS grade, were acquired from Merck (Darmstadt, Germany). All kits for the determination of biochemical indicators (ALT, AST, ALP, TBIL, SOD, CAT, GSH, and MDA) were supplied by Nanjing Jiancheng Bioengineering Institute (Nanjing, China). BCA kit was provided by BioSharp (Hefei, China). ELISA kit was obtained from Multi Sciences Biotech Company (Hangzhou,
Qualitative and quantitative assay of polyphenols
The chemical compositions of the ethanol extract were determined qualitatively and quantitatively by UHPLC-ESI-HRMS/MS. Fig. 2 showed that the total ion current chromatogram in negative mode. Table 1 exhibited that 11 compounds were identified from the extract, including two organic acids (1,2), and nine phenolics (3–11). Quantitative analysis presented that gallic acid (3) and quercetin-3-O-rhamnoside (8) were the compounds with the highest content in the extracts, with contents of
Discussion
At present, TB remains a major global health hotspot, particularly in developing countries (Martini et al., 2018). Before COVID-19, TB was the leading cause of infectious disease death worldwide (Dartois and Rubin, 2022). INH and RIF are effective clinical first-line anti-TB agents, and long-term combination of these drugs can cause DILI (Kheora and Rana, 2022). Due to no specific medicine for liver injury caused by anti-TB drugs, during the treatment, the match to protect liver medicine and
Conclusions
This paper demonstrated that the extract from Rhus chinensis Mill. fruits had a strong preventive effect on liver damage caused by INH/RIF. The crucial mechanism of the extract on INH/RIF caused liver damage was through the activation of Nrf2 signaling pathway and down-regulating the expression of CYP2E1. Moreover, the extract may inhibit inflammatory responses by decreasing the secretion of IL-1β, TNF-α and IL-6, and prevent apoptosis via adjusting the expression of key apoptosis proteins
Ethics statement
Animal experiments in the present work were performed in strict compliance with the Guidelines for the Care and Use of Laboratory Animals and authorized by the Ethics Committee of Animal Experiments of Kunming University of Science and Technology.
Funding and acknowledgments
The present work was financially supported by the National Natural Science Foundation of China (Grant No. 31960477), and Major Science and Technology Project of the Science and Technology Department of Yunnan Province (Grant Nos. 202202AG050009, 202102AE090050 and 202102AE090025).
Ethics statement
On behalf of, and having obtained permission from all the authors, I declare that:
- 1.
The paper has not been published in whole or in part elsewhere;
- 2.
The paper is not currently being considered for published elsewhere;
- 3.
All authors have been personally and actively involved in substantive work leading to the report, and will hold themselves jointly and individually responsible for its content.
- 4.
All animal procedures were conducted in strict accordance with the National Institutes of Health Guide for the
CRediT authorship contribution statement
Yilin Sun: Investigation, Data curation, Writing – original draft, All authors have read and approved the final version of the manuscript. Yuanyue Zhang: Methodology, All authors have read and approved the final version of the manuscript. Nan Ma: Writing – review & editing. Shengbao Cai: Conceptualization, Funding acquisition, Supervision, All authors have read and approved the final version of the manuscript.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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