基于数据挖掘的药物性肝损伤动物模型应用特点分析
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国家自然科学基金面上项目(82074340);河南省重大专项(221100310400);河南省重点研发与推广专项(科技攻关)(242102310534);河南省中医学“双一流”创建科学研究专项(HSRP-DFCTCM-2023-7-25)


Application Characteristics of Drug-induced Liver Injury Animal Models Based on Data Mining
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    摘要:

    目的:药物性肝损伤(DILI)是临床常见的肝脏疾病,鉴于相关的动物实验模型与临床症状贴合度较低,复制更符合临床实际的DILI模型仍需深入研究。通过对2000年1月至2023年7月DILI动物模型相关数据分析归纳总结,为构建与人类发病机制、与人体肝脏代谢功能更接近临床实际的动物模型提供参考。方法:检索并筛选DILI动物模型相关文献资料,建立数据库并对文献资料中涉及的造模动物、造模方法、成模时间、阳性药物、检测指标等进行归纳和分析。结果:在DILI动物模型中小鼠占比74.14%,其中C57BL/6小鼠占比27.41%,KM小鼠占比25.07%,ICR小鼠占比10.70%及Balb/c小鼠占比7.57%。对乙酰氨基酚为最常用造模药物占比63.57%。对所纳入文献中的常用造模药对乙酰氨基酚造模剂量进行统计分析,发现小鼠造模剂量最多的是300 mg/kg,占比31.46%;大鼠的造模剂量多为1 000 mg/kg。最常用的造模时间是24 h,占比40%;其次是12 h,占比23.24%;再次是6 h,占比16.22%。最常用的给药途径是腹腔注射,占比56.87%;其次是灌胃占比41.51%。常用的检测指标的方法有蛋白质印迹法,占比27.45%;其次是实时荧光定量PCR占比26.61%。主要用来检测血清谷丙转氨酶(GPT)、谷草转氨酶(GOT)、碱性磷酸酶(ALP)、总胆红素(TBIL)等指标的变化。最常用阳性对照药物为水飞蓟素,占比37.61%;其次为N-乙酰半胱氨酸(NAC)和联苯双酯,占比分别为27.52%和26.61%。通过对所选造模条件进行赋值权重,提出最佳模型为6~8周的雄性C57BL/6小鼠,一次性腹腔注射对乙酰氨基酚300 mg/kg,24 h后检测小鼠的表观指征群、血清和肝脏等各项指标,均符合临床表现即为造模成功,最佳模型占比56.42%。以6~8周的雄性C57BL/6小鼠为模型开展实验研究,采用一次性腹腔注射对乙酰氨基酚300 mg/kg建立DILI模型,通常24 h后即可造模成功;选用水飞蓟素、N-乙酰半胱氨酸或联苯双酯作为阳性对照药;用蛋白质印迹法、实时荧光定量PCR、ELISA等方法检测血清的谷丙转氨酶(GPT)、谷草转氨酶(GOT)、碱性磷酸酶(ALP)、总胆红素(TBIL)等水平,结合肝脏指数、肝组织病理学结果作为模型建立、检测与评价的最佳指标。结论:通过文献挖掘和系统化分析,对既往DILI模型建立规律及潜在问题进行归纳,筛选出DILI动物模型复制的最佳条件和评价指标,为建立临床吻合度高且重复性好的DILI动物模型提供参考。

    Abstract:

    Drug-induced liver injury(DILI) is a common clinical liver disease.Given the low correlation between existing animal experimental models and clinical symptoms,further research is needed to replicate a DILI model that better reflects the clinical reality.This study aims to analyze and summarize the relevant data of DILI animal models from January 2000 to July 2023,providing references for constructing animal models that are closer to human pathogenesis and liver metabolic functions in clinical practice.Methods:Relevant literature on DILI animal models was searched and selected.A database was created,and the animals used for modeling,modeling methods,modeling duration,positive drugs,and detection indicators were summarized and analyzed.Results:Mice accounted for 74.14% of DILI animal models,with C57BL/6 mice accounting for 27.41%,KM mice for 25.07%,ICR mice for 10.70%,and Balb/c mice for 7.57%.Acetaminophen was the most commonly used drug,accounting for 63.57%.A statistical analysis of the modeling doses for acetaminophen in the included studies showed that the most common dose for mice was 300 mg/kg,accounting for 31.46%,while the most common dose for rats was 1 000 mg/kg.The most common modeling time was 24 h(40%),followed by 12 h(23.24%) and 6 h(16.22%).The most commonly used administration route was intraperitoneal injection(56.87%),followed by gavage(41.51%).Common detection methods included Western blot(27.45%) and real-time PCR(26.61%).The main indicators measured were serum glutamic-pyruvic transaminase(GPT),glutamic-oxaloacetic transaminase(GOT),alkaline phosphatase(ALP),and total bilirubin(TBIL).The most common positive control drug was silymarin(37.61%),followed by N-acetylcysteine(NAC) and biphenyl dimethyl dicarboxylate(26.61% and 27.52%,respectively).By assigning weights to the selected modeling conditions,the optimal model was determined to be male C57BL/6 mice aged 6 to 8 weeks,with a single intraperitoneal injection of acetaminophen at 300 mg/kg.After 24 h,the mice's observable indicators,serum,liver,and other measures should be evaluated to match clinical symptoms,indicating successful model creation.This optimal model accounted for 56.42%.Using male C57BL/6 mice aged 6 to 8 weeks,a single intraperitoneal injection of acetaminophen at 300 mg/kg successfully establishes the DILI model within 24 h.Silymarin,NAC,or biphenyl dimethyl dicarboxylate can be used as positive controls.Detection methods such as Western blot,real-time PCR,and ELISA are employed to assess serum levels of GPT,GOT,ALP,TBIL,and combined liver index and histological results to evaluate model establishment,detection,and evaluation indicators.Conclusion:Through literature mining and systematic analysis,the past patterns and potential issues of DILI model establishment were summarized,and the optimal conditions and evaluation indicators for replicating DILI animal models were identified.This provides a reference for creating DILI animal models with high clinical relevance and reproducibility.

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金淼鑫,赵晖,朱平生,苗明三,乔靖怡.基于数据挖掘的药物性肝损伤动物模型应用特点分析[J].世界中医药,2025,(01).

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  • 收稿日期:2024-04-30
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  • 在线发布日期: 2025-03-30
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