Parallelogram Approach Using Rat-Human In Vitro and Rat In Vivo Toxicogenomics Predicts Acetaminophen-induced Hepatotoxicity in Humans
Parallelogram Approach Using Rat-Human In Vitro and Rat In Vivo Toxicogenomics Predicts Acetaminophen-induced Hepatotoxicity in Humans
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DOI：
10.1093/toxsci/kfn237
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发表时间：
2009-02-01
影响因子：
3.8
通讯作者：
van Delft, Joost H. M.
中科院分区：
文献类型：
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作者：
Kienhuis, Anne S.;van de Poll, Marcel C. G.;van Delft, Joost H. M.
在药理学和毒理学研究中经常使用啮齿类动物肝脏体外系统，这对将体外结果外推至体内情况以及从啮齿类动物至人类的种间外推提出了挑战。毒理基因组学的方法可能有助于评估这些模型系统的相关性，通过直接比较毒物诱导的基因表达谱和推断几个系统之间的机制，对人类的风险评估。在本研究中，对乙酰氨基酚（APAP）被用作模型化合物，以比较大鼠和人类之间的基因表达反应，使用体外细胞模型，肝细胞，以及大鼠在体外和体内。在调节的生化途径和生物过程的水平上进行比较，而不是在单个基因的水平上进行比较，似乎是更可取的，因为它增加了各种系统之间的重叠。T-profiler的途径分析揭示了在体外大鼠和人肝细胞中以及在体外和体内大鼠肝脏中抑制的相似的生化途径和生物过程。抑制途径包括能量消耗的生化途径，线粒体功能和氧化还原酶活性。本研究是第一个使用基于毒理学的毒理学方法，在体外外推到体内和种间，以揭示相关的机制，表明APAP诱导的肝毒性在人体内。
The frequent use of rodent hepatic in vitro systems in pharmacological and toxicological investigations challenges extrapolation of in vitro results to the situation in vivo and interspecies extrapolation from rodents to humans. The toxicogenomics approach may aid in evaluating relevance of these model systems for human risk assessment by direct comparison of toxicant-induced gene expression profiles and infers mechanisms between several systems. In the present study, acetaminophen (APAP) was used as a model compound to compare gene expression responses between rat and human using in vitro cellular models, hepatocytes, and between rat in vitro and in vivo. Comparison at the level of modulated biochemical pathways and biological processes rather than at that of individual genes appears preferable as it increases the overlap between various systems. Pathway analysis by T-profiler revealed similar biochemical pathways and biological processes repressed in rat and human hepatocytes in vitro, as well as in rat liver in vitro and in vivo. Repressed pathways comprised energy-consuming biochemical pathways, mitochondrial function, and oxidoreductase activity. The present study is the first that used a toxicogenomics-based parallelogram approach, extrapolating in vitro to in vivo and interspecies, to reveal relevant mechanisms indicative of APAP-induced liver toxicity in humans in vivo.