Kienhuis Anne S, van de Poll Marcel C G, Wortelboer Heleen, van Herwijnen Marcel, Gottschalk Ralph, Dejong Cornelis H C, Boorsma André, Paules Richard S, Kleinjans Jos C S, Stierum Rob H, van Delft Joost H M
Department of Health Risk Analysis and Toxicology, Maastricht University, Maastricht, The Netherlands.
Toxicol Sci. 2009 Feb;107(2):544-52. doi: 10.1093/toxsci/kfn237. Epub 2008 Nov 12.
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.
在药理学和毒理学研究中频繁使用啮齿动物肝脏体外系统，这对将体外结果外推至体内情况以及从啮齿动物到人类的种间外推提出了挑战。毒理基因组学方法可能有助于通过直接比较毒物诱导的基因表达谱并推断多个系统之间的机制，来评估这些模型系统对人类风险评估的相关性。在本研究中，对乙酰氨基酚（APAP）被用作模型化合物，以使用体外细胞模型、肝细胞比较大鼠和人类之间的基因表达反应，以及大鼠体外和体内之间的基因表达反应。在调节的生化途径和生物学过程水平而非单个基因水平进行比较似乎更可取，因为这会增加不同系统之间的重叠。通过T-profiler进行的通路分析显示，在体外大鼠和人类肝细胞以及体外和体内大鼠肝脏中，相似的生化途径和生物学过程受到抑制。受抑制的途径包括耗能生化途径、线粒体功能和氧化还原酶活性。本研究首次使用基于毒理基因组学的平行四边形方法，从体外外推至体内以及种间外推，以揭示指示APAP在人类体内诱导肝毒性的相关机制。
