Toxicant-Induced Metabolic Alterations in Lipid and Amino Acid Pathways Are Predictive of Acute Liver Toxicity in Rats.
Toxicant-Induced Metabolic Alterations in Lipid and Amino Acid Pathways Are Predictive of Acute Liver Toxicity in Rats.
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毒物诱导的脂质和氨基酸途径代谢改变可预测大鼠急性肝毒性。
DOI：
10.3390/ijms21218250
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发表时间：
2020-11-04
影响因子：
5.6
通讯作者：
Wallqvist A
中科院分区：
文献类型：
--
作者：
Pannala VR;Estes SK;Rahim M;Trenary I;O'Brien TP;Shiota C;Printz RL;Reifman J;Shiota M;Young JD;Wallqvist A
与肝细胞代谢异常相关的肝脏疾病和病症可通过药物和环境毒物暴露引发。在这项研究中，我们测试了这样的假设：基因和代谢谱可以揭示肝脏对不同毒物反应的共性，并提供识别急性肝脏毒性早期特征的能力。我们使用了Sprague道利大鼠和三种典型的肝毒物：对乙酰氨基酚（2 g/kg）、溴苯（0.4 g/kg）和四氯化碳（0.3 g/kg），以确定单次急性暴露剂量后肝脏代谢的早期扰动。我们在两个时间点（5和10小时）测量了肝脏基因和血浆代谢物的变化，并使用基因组规模的代谢模型来确定三种毒物的肝脏反应的共性。我们发现了强相关性的基因和代谢谱之间的毒物，在肝脏反应毒性的相似性。我们确定了几个损伤特定的途径，在脂质和氨基酸代谢的变化类似的三种毒物。我们的研究结果表明，脂质和氨基酸代谢中的几种血浆代谢物与肝毒性的进展密切相关，因此，可以靶向和临床评估其作为急性肝毒性早期预测因子的潜力。
Liver disease and disorders associated with aberrant hepatocyte metabolism can be initiated via drug and environmental toxicant exposures. In this study, we tested the hypothesis that gene and metabolic profiling can reveal commonalities in liver response to different toxicants and provide the capability to identify early signatures of acute liver toxicity. We used Sprague Dawley rats and three classical hepatotoxicants: acetaminophen (2 g/kg), bromobenzene (0.4 g/kg), and carbon tetrachloride (0.3 g/kg), to identify early perturbations in liver metabolism after a single acute exposure dose. We measured changes in liver genes and plasma metabolites at two time points (5 and 10 h) and used genome-scale metabolic models to identify commonalities in liver responses across the three toxicants. We found strong correlations for gene and metabolic profiles between the toxicants, indicative of similarities in the liver response to toxicity. We identified several injury-specific pathways in lipid and amino acid metabolism that changed similarly across the three toxicants. Our findings suggest that several plasma metabolites in lipid and amino acid metabolism are strongly associated with the progression of liver toxicity, and as such, could be targeted and clinically assessed for their potential as early predictors of acute liver toxicity.
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影响因子：
29.4
作者：
Luedde T;Kaplowitz N;Schwabe RF
通讯作者：
Schwabe RF
影响因子：
1.5
作者：
Al-Eryani L;Wahlang B;Falkner KC;Guardiola JJ;Clair HB;Prough RA;Cave M
通讯作者：
Cave M
影响因子：
4.1
作者：
Chen, I-Shu;Chen, Yi-Chen;Chiu, Chih-Hsien
通讯作者：
Chiu, Chih-Hsien
影响因子：
0.9
作者：
Jang, J. H.;Kang, K. J.;Lee, I. S.
通讯作者：
Lee, I. S.
DOI：
10.1002/prca.201600123
发表时间：
2017-01
期刊：
Proteomics. Clinical applications
影响因子：
--
作者：
Gao Y;Cao Z;Yang X;Abdelmegeed MA;Sun J;Chen S;Beger RD;Davis K;Salminen WF;Song BJ;Mendrick DL;Yu LR
通讯作者：
Yu LR