背景:补骨脂。BGZ是治疗肾阳虚证的常用中药,具有良好的疗效和安全性。然而,近年来,BGZ也有引起肝损伤的报道。根据中医理论,服用BGZ可能会在肾阴虚证(Yinsyn)患者中引起一系列不良反应,提示BGZ引起的肝损害可能与其临床不合理使用有关。
目的:中药致肝损伤是一种罕见但潜在严重的药物不良反应,而对药物性肝损伤(DILI)易感个体的鉴定仍然具有挑战性.本研究旨在研究Yangsyn和Yinsyn大鼠模型对BGZ的差异反应,并确定相应的特征性生物标志物。
方法:分别用氢化可的松和甲状腺素+利血平诱导了相应的杨精和银精动物模型。体重,器官指数,血清生物化学,苏木素和伊红(HE)染色用于评估BGZ对Yangsyn和Yinsyn大鼠的肝毒性作用。用转录组学和代谢组学方法筛选了BGZ改变的具有代表性的生物标志物(包括代谢产物和差异表达基因(DEGs)),分别。
结果:肝脏器官指数的水平变化,丙氨酸氨基转移酶(ALT),和天冬氨酸氨基转移酶(AST),提示BGZ对杨森和银森大鼠具有肝保护和肝损伤作用,分别,肝组织的病理变化也证实了这一结果。结果表明,102个DEGs和27个代谢物与BGZ对杨精的保护作用显著相关,主要与甘油磷脂代谢有关,花生四烯酸代谢,泛酸,和辅酶A(CoA)生物合成途径。虽然28个DEG和31个代谢物,与泛酸和CoA生物合成途径有关,对BGZ诱导的肝损伤有显著调节作用。此外,4DEGs(醛脱氢酶1家族成员B1(Aldh1b1),溶质载体家族25成员25(Slc25a25),Pim-3原癌基因,丝氨酸/苏氨酸激酶(Pim3),首先是同源物(Oaf)和4种代谢物(磷脂,磷脂酰胆碱,N-乙酰亮氨酸,Yangsyn组中的胆绿素)和1DEG[半乳糖凝集素5(Lgals5)]和1个代谢物(5-氨基-1-(5-磷酸-D-核糖基)咪唑-4-羧酸酯)与BGZ处理组和未处理组的ALT和AST水平(接受者工作特性(ROC)≥0.9)。
结论:银参和洋参分别是BGZ发挥肝损伤和肝保护作用的易感综合征。主要与氨基酸代谢的调节有关,脂质代谢,能量代谢,以及辅因子和维生素的代谢。结果进一步表明,在使用与调节能量代谢有关的药物时,应注意选择易感人群,基于中医证候理论的银参/养参动物模型可能是一种识别易感人群接受中医治疗的可行方法。
BACKGROUND: Psoralea corylifolia Linn. (BGZ) is a commonly used traditional Chinese medicine (TCM) for the treatment of kidney-yang deficiency syndrome (Yangsyn) with good curative effect and security. However, BGZ was also reported to induce liver injury in recent years. According to TCM theory, taking BGZ may induce a series of adverse reactions in patients with kidney-yin deficiency syndrome (Yinsyn), which suggests that BGZ-induced liver damage may be related to its unreasonable clinical use.
OBJECTIVE: Liver injury caused by TCM is a rare but potentially serious adverse drug reaction, and the identification of predisposed individuals for drug-induced liver injury (DILI) remains challenging. The study aimed to investigate the differential responses to BGZ in Yangsyn and Yinsyn rat models and identify the corresponding characteristic biomarkers.
METHODS: The corresponding animal models of Yangsyn and Yinsyn were induced by hydrocortisone and thyroxine + reserpine respectively. Body weight, organ index, serum biochemistry, and Hematoxylin and Eosin (HE) staining were used to evaluate the liver toxicity effect of BGZ on rats with Yangsyn and Yinsyn. Transcriptomics and metabonomics were used to screen the representative biomarkers (including metabolites and differentially expressed genes (DEGs)) changed by BGZ in Yangsyn and Yinsyn rats, respectively.
RESULTS: The level changes of liver organ index, alanine aminotransferase (ALT), and aspartate aminotransferase (AST), suggested that BGZ has liver-protective and liver-damaging effects on Yangsyn and Yinsyn rats, respectively, and the results also were confirmed by the pathological changes of liver tissue. The results showed that 102 DEGs and 27 metabolites were significantly regulated related to BGZ\'s protective effect on Yangsyn, which is mainly associated with the glycerophospholipid metabolism, arachidonic acid metabolism, pantothenate, and coenzyme A (CoA) biosynthesis pathways. While 28 DEGs and 31 metabolites, related to the pathway of pantothenate and CoA biosynthesis, were significantly regulated for the BGZ-induced liver injury in Yinsyn. Furthermore, 4 DEGs (aldehyde dehydrogenase 1 family member B1 (Aldh1b1), solute carrier family 25 member 25 (Slc25a25), Pim-3 proto-oncogene, serine/threonine kinase (Pim3), out at first homolog (Oaf)) and 4 metabolites (phosphatidate, phosphatidylcholine, N-Acetylleucine, biliverdin) in the Yangsyn group and 1 DEG [galectin 5 (Lgals5)] and 1 metabolite (5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxylate) in Yinsyn group were significantly correlated to the ALT and AST levels of BGZ treated and untreated groups (receiver operating characteristic (ROC) ≥ 0.9).
CONCLUSIONS: Yinsyn and Yangsyn are the predisposed syndromes for BGZ to exert liver damage and liver protection respectively, which are mainly related to the regulation of amino acid metabolism, lipid metabolism, energy metabolism, and metabolism of cofactors and vitamins. The results further suggest that attention should be paid to the selection of predisposed populations when using drugs related to the regulation of energy metabolism, and the Yinsyn/Yangsyn animal models based on the theory of TCM syndromes may be a feasible method for identifying the susceptible population to receive TCM.