Abstract：
Furan is a chemical hepatocarcinogen in mice and rats. Its previously postulated cancer mode of action (MOA) is chronic cytotoxicity followed by sustained regenerative proliferation; however, its molecular basis is unknown. To this end, we conducted toxicogenomic analysis of B3C6F1 mouse livers following three week exposures to non-carcinogenic (0, 1, 2mg/kgbw) or carcinogenic (4 and 8mg/kgbw) doses of furan. We saw enrichment for pathways responsible for cytotoxicity: stress-activated protein kinase (SAPK) and death receptor (DR5 and TNF-alpha) signaling, and proliferation: extracellular signal-regulated kinases (ERKs) and TNF-alpha. We also noted the involvement of NF-kappaB and c-Jun in response to furan, which are genes that are known to be required for liver regeneration. Furan metabolism by CYP2E1 produces cis-2-butene-1,4-dial (BDA), which is required for ensuing cytotoxicity and oxidative stress. NRF2 is a master regulator of gene expression during oxidative stress and we suggest that chronic NFR2 activity and chronic inflammation may represent critical transition events between the adaptive (regeneration) and adverse (cancer) outcomes. Another objective of this study was to demonstrate the applicability of toxicogenomics data in quantitative risk assessment. We modeled benchmark doses for our transcriptional data and previously published cancer data, and observed consistency between the two. Margin of exposure values for both transcriptional and cancer endpoints were also similar. In conclusion, using furan as a case study we have demonstrated the value of toxicogenomics data in elucidating dose-dependent MOA transitions and in quantitative risk assessment.
摘要：
呋喃是小鼠和大鼠中的化学肝癌原。其先前假定的癌症作用模式（MOA）是慢性细胞毒性，随后是持续的再生增殖；然而，它的分子基础是未知的。为此,我们在暴露于非致癌剂量(0,1,2mg/kgbw)或致癌剂量(4和8mg/kgbw)呋喃3周后,对B3C6F1小鼠肝脏进行了毒理学分析.我们看到了细胞毒性通路的富集：应激激活蛋白激酶（SAPK）和死亡受体（DR5和TNF-α）信号，和增殖:细胞外信号调节激酶(ERKs)和TNF-α。我们还注意到NF-kappaB和c-Jun参与对呋喃的反应，这些基因是肝脏再生所必需的。CYP2E1的呋喃代谢产生顺式-2-丁烯-1,4-二（BDA），这是随之而来的细胞毒性和氧化应激所必需的。NRF2是氧化应激过程中基因表达的主要调节因子，我们认为慢性NFR2活性和慢性炎症可能代表适应性（再生）和不良（癌症）结果之间的关键过渡事件。本研究的另一个目的是证明毒性基因组学数据在定量风险评估中的适用性。我们为转录数据和以前发表的癌症数据建立了基准剂量模型，并观察到两者之间的一致性。转录和癌症终点的暴露值的边缘也相似。总之,使用呋喃作为案例研究，我们已经证明了毒性基因组学数据在阐明剂量依赖性MOA转换和定量风险评估中的价值。
