Abstract
Oleanolic acid (OA), a natural triterpenoid, which has the development prospects in anti-tumor therapy is a widely used hepatoprotective drug in China. It has been reported that OA can cause liver toxicity after higher doses or longer-term use. Therefore, the study aims to explore the possible hepatotoxicity mechanism based on liver metabolic profiles. Liver metabolic profiles were obtained from untargeted ultrahigh performance liquid chromatography (UHPLC)-Q Exactive Orbitrap mass spectrometry (MS) technique. It was found that altered bile acid, amino acid, and energy metabolism might be at least partly responsible for OA-induced hepatotoxicity. Bile acid metabolism, as the most important pathway, was verified by using UHPLC-TSQ-MS, indicating that conjugated bile acids were the main contributors to OA-induced liver toxicity. Our findings confirmed that increased bile acids were the key element of OA hepatotoxicity, which may open new insights for OA hepatotoxicity in-depth investigations, as well as provide a reference basis for more hepatotoxic drug mechanism research.
Highlights
Drug-induced liver injury (DILI) is the primary factor of drug withdrawal and the incidence is increasing (Oh et al, 2015), including hepatocellular pattern, cholestatic pattern, and mixed pattern
Combined with the endogenous substances, biochemical analysis, and gallbladder morphology, bile acid components were investigated by targeted metabolomics, the results unmasked that increased bile acids were the main factor leading to Oleanolic acid (OA) hepatotoxicity
The liver plays a crucial role in amino acid metabolism, it is responsible for a large part of the overall amino acid synthesis and catabolism
Summary
Drug-induced liver injury (DILI) is the primary factor of drug withdrawal and the incidence is increasing (Oh et al, 2015), including hepatocellular pattern, cholestatic pattern, and mixed pattern. The hepatotoxicity of Polygoni Multiflori Radix is related to activity inhibition of cytochrome P450 1A2 (CYP1A2) or cytochrome P450 2E1 (CYP2E1) (Deng et al, 2017), as well as complex composition and patient factors (Wei et al, 2019). It is a challenge in managing DILI, especially when the mechanism is unknown (Chen et al, 2015; Chatterjee and Annaert, 2018). Understanding the mechanism is essential for predicting and clinically managing drug toxicity.
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