摘要
传统中药雷公藤是临床上的常用药物,具有祛风湿、杀虫解毒、消肿止痛、活血通络的功效。现代药理学表明,雷公藤具有抗炎、抗肿瘤和免疫抑制等药理作用。现广泛用于自身免疫性疾病、肾脏性疾病和肿瘤等疾病的治疗。雷公藤具有多种化学成分,其中雷公藤甲素(TP)对人体消化、循环、生殖等系统均具有不同程度的损害,以肝损伤最常见,这极大的限制了TP在新药研发和产业化应用中的拓展空间。因此,笔者聚焦于TP致肝损伤这一研究热点,针对TP致肝损伤的临床表现、损伤机制及减毒策略进行国内外相关文献的检索和整理,这有助于为TP的临床用药安全性和科学用药监管提供科学依据。TP致肝损伤的临床表现多为氨基转移酶异常、食欲不振、恶心呕吐、纳差、皮肤和巩膜黄染、小便黄等。以上临床表现的机制涉及细胞凋亡、氧化应激、影响细胞色素P450超家族、巨噬细胞极化和生物钟基因Clock调控等几个方面。其中细胞凋亡与神经源性位点缺口同系物蛋白1(Notch1)、动力蛋白相关蛋白1(Drp1)-细胞色素C(Cyt C)、磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B(Akt)、丝裂原活化蛋白激酶(MAPK)、肿瘤抑制蛋白53(p53)、FAS细胞表面死亡受体(Fas)/Caspase-8等信号通路有关;氧化应激与抑制核转录因子E2相关因子(NRF2)信号通路、促进细胞色素P4502E1(CYP2E1)表达引发活性氧(ROS)过度积累等有关;对细胞色素P450超家族的影响表现为:降低细胞色素P4503A(CYP3A)、细胞色素P4502C9(CYP2C9)、细胞色素P4502C19(CYP2C19)、细胞色素P4501A2(CYP1A2)等的底物亲和力、活性和表达;促进巨噬细胞向M1型转化与引发炎症因子分泌和内毒素积累有关;机体内在的生物钟基因Clock的节律性调控与影响细胞色素P4503A11(CYP3A11)代谢酶的表达有关。临床应用中的减毒策略包括炮制减毒和配伍减毒法,有助于减毒的中药及单体成分包括甘草、白芍、金钱草、绿豆、生地黄、藏红花素和芍药苷等。通过对上述内容进行综述和探讨,为TP的相关研究和临床应用提供更多参考。
As a commonly used traditional Chinese medicine in clinical practice,Tripterygium wilfordii has the functions of dispelling wind and removing dampness,detoxicating and destroying parasites,detumescence,pain relief,promoting blood circulation,and dredging collateral.Modern pharmacological studies show that it also has other functions such as anticancer,anti-inflammation,and immunosuppression.It has been widely used to treat autoimmune diseases,renal diseases,and tumors.T.wilfordii contains a variety of chemical components,among which triptolide(TP)can cause varying degrees of damage to human digestive,circulatory,reproductive,and other systems,with liver injury being the most common one,which greatly limits the development of TP in new drug research and industrial application.Therefore,the authors focused on the research hotspot of TP-induced liver injury and summarized relevant Chinese and international literature regarding the clinical manifestations,injury mechanisms,and detoxification strategies of TP-induced liver injury.This helps to provide a scientific basis for the clinical drug safety and scientific drug supervision of TP.The clinical manifestations of TP-induced liver injury are mostly abnormal transaminases,loss of appetite,nausea and vomiting,anorexia,yellow staining of skin and sclera,and yellow urine.The mechanisms of the above clinical manifestations involve apoptosis,oxidative stress,influence on cytochrome P450 superfamily,macrophage polarization,regulation of biological clock gene Clock,etc.Among them,cell apoptosis is related to neurogenic locus notch homolog protein 1(Notch1),dynamin-related protein 1(Drp1)-cytochrome C(Cyt C),phosphatidylinositide 3-kinases(PI3K)/protein kinase B(Akt),mitogen-activated protein kinase(MAPK),tumor suppressor protein 53(p53),Fas cell surface death receptor(Fas)/Caspase-8,and other signaling pathways.Oxidative stress is related to inhibition of nuclear factor-erythroid 2-related factor 2(NRF2)signaling pathway,promotion of cytochrome P4502E1(CYP2E1)expression,and excessive accumulation of reactive oxygen(ROS).The influence of the cytochrome P450 superfamily is manifested as reducing the substrate affinity,activity,and expression of cytochrome P4503A(CYP3A),cytochrome P4502C9(CYP2C9),cytochrome P4502C19(CYP2C19),and cytochrome P4501A2(CYP1A2).Promoting the transformation of macrophages into the M1 type is related to the secretion of inflammatory factors and the accumulation of endotoxin,and the internal rhythmic regulation of the biological clock gene Clock,is related to the expression of cytochrome P4503A11(CYP3A11)metabolic enzyme.The detoxification strategies in the clinical application include herbs-processing detoxification strategy and drug-pairing detoxification.The traditional Chinese medicines and monomers that are helpful for detoxification include Glycyrrhiza uralensis,Paeonia lactiflora,Lysimachia christinae,Rehmannia glutinosa,saffron,and paeoniflorin.The reviews and discussion about these topics can help to provide more references for related research and clinical application of TP.
作者
王婷
孙珂
李静颐
周雅丽
李红梅
WANG Ting;SUN Ke;LI Jingyi;ZHOU Yali;LI Hongmei(School of Life Science,Beijing University of Chinese Medicine,Beijing 100029,China)
出处
《中国实验方剂学杂志》
CAS
CSCD
北大核心
2024年第6期196-204,共9页
Chinese Journal of Experimental Traditional Medical Formulae
基金
北京市科学技术委员会干细胞与再生医学研究专项(Z191100001519006)
国家自然科学基金青年科学基金项目(81903955)。
关键词
雷公藤甲素
肝损伤
临床特征
机制
减毒策略
triptolide
liver injury
clinical features
mechanism
detoxification strategies
