Serum metabolomics reveals irreversible inhibition of fatty acid beta-oxidation through the suppression of PPARalpha activation as a contributing mechanism of acetaminophen-induced hepatotoxicity.
Serum metabolomics reveals irreversible inhibition of fatty acid beta-oxidation through the suppression of PPARalpha activation as a contributing mechanism of acetaminophen-induced hepatotoxicity.
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DOI：
10.1021/tx800464q
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发表时间：
2009-04
影响因子：
4.1
通讯作者：
Gonzalez, Frank J.
中科院分区：
文献类型：
--
作者：
Chen, Chi;Krausz, Kristopher W.;Shah, Yatrik M.;Idle, Jeffrey R.;Gonzalez, Frank J.
对乙酰氨基酚（APAP）过量后，代谢生物活化、谷胱甘肽耗竭和共价结合是早期标志性事件。然而，导致APAP诱导的肝坏死和细胞凋亡的后续代谢结果尚未完全阐明。在这项研究中，对照组和APAP治疗的野生型和Cyp 2 e1基因敲除小鼠的血清代谢组进行了检查，通过液相色谱-质谱法（LC-MS）和多变量数据分析。剂量反应研究表明，血清中长链酰基肉毒碱的积累有助于在多变量模型中将经历APAP诱导的肝毒性的野生型小鼠与其他小鼠组分离。该观察结果与APAP处理的野生型小鼠血清中甘油三酯和游离脂肪酸的增加相结合，表明APAP处理可以破坏脂肪酸β-氧化。一项时间进程研究进一步表明，野生型和Cyp 2 e1基因敲除小鼠的血清酰基肉毒碱水平在APAP治疗的早期明显升高。虽然在野生型小鼠中保持高水平，但在24小时治疗结束时，Cyp 2 e1缺失小鼠的血清酰基肉毒碱水平逐渐恢复正常。与血清转氨酶活性和肝脏谷胱甘肽水平不同，血清酰基肉毒碱积累的模式表明，酰基肉毒碱可以作为监测APAP诱导的肝毒性的补充生物标志物。通过比较野生型和Ppara基因敲除小鼠对空腹激发的代谢组学反应，确定了过氧化物酶体增殖物激活受体α（PPARα）在调节血清酰基肉毒碱水平中的重要作用。APAP处理后，野生型小鼠中的PPARα活性上调是短暂的，但Cyp 2 e1基因敲除小鼠中的上调时间更长。总体而言，APAP诱导的肝毒性的血清代谢组学显示，APAP治疗后CYP 2 E1介导的代谢活化和氧化应激可导致脂肪酸氧化的不可逆抑制，可能通过抑制PPARα调节途径。
Metabolic bioactivation, glutathione depletion and covalent binding are the early hallmark events after acetaminophen (APAP) overdose. However, the subsequent metabolic consequences contributing to APAP-induced hepatic necrosis and apoptosis have not been fully elucidated. In this study, serum metabolomes of control and APAP-treated wild-type and Cyp2e1-null mice were examined by liquid chromatography-mass spectrometry (LC-MS) and multivariate data analysis. A dose-response study showed that the accumulation of long-chain acylcarnitines in serum contributes to the separation of wild-type mice undergoing APAP-induced hepatotoxicity from other mouse groups in a multivariate model. This observation, in conjunction with the increase of triglycerides and free fatty acids in the serum of APAP-treated wild-type mice, suggested that APAP treatment can disrupt fatty acid β-oxidation. A time course study further indicated that both wild-type and Cyp2e1-null mice had their serum acylcarnitine levels markedly elevated within the early hours of APAP treatment. While remaining high in wild-type mice, serum acylcarnitine levels gradually returned to normal in Cyp2e1-null mice at the end of the 24 h treatment. Distinct from serum aminotransferase activity and hepatic glutathione levels, the pattern of serum acylcarnitine accumulation suggested that acylcarnitines can function as complementary biomarkers for monitoring the APAP-induced hepatotoxicity. An essential role for peroxisome proliferator-activated receptor α (PPARα) in the regulation of serum acylcarnitine levels was established by comparing the metabolomic responses of wild-type and Ppara-null mice to a fasting challenge. The upregulation of PPARα activity following APAP treatment was transient in wild-type mice, but was much more prolonged in Cyp2e1-null mice. Overall, serum metabolomics of APAP-induced hepatotoxicity revealed that the CYP2E1-mediated metabolic activation and oxidative stress following APAP treatment can cause irreversible inhibition of fatty acid oxidation, potentially through suppression of PPARα-regulated pathways.
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影响因子：
168.9
作者：
Bernal, W;Donaldson, N;Wendon, J
通讯作者：
Wendon, J
影响因子：
3.9
作者：
Cheung, C;Yu, AM;Gonzalez, FJ
通讯作者：
Gonzalez, FJ
DOI：
10.1006/faat.1996.0026
发表时间：
1996-02-01
期刊：
FUNDAMENTAL AND APPLIED TOXICOLOGY
影响因子：
--
作者：
Manautou, JE;Hart, SGE;Cohen, SD
通讯作者：
Cohen, SD
影响因子：
3.8
作者：
MEYERS, LL;BEIERSCHMITT, WP;COHEN, SD
通讯作者：
COHEN, SD
影响因子：
4.2
作者：
Nowaczyk, MJM;Whelan, D;Pollitt, RJ
通讯作者：
Pollitt, RJ