Comparative NMR-based metabonomic investigation of the metabolic phenotype associated with tienilic acid and tienilic acid isomer.
Comparative NMR-based metabonomic investigation of the metabolic phenotype associated with tienilic acid and tienilic acid isomer.
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DOI：
10.1021/tx3002803
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发表时间：
2012-11
影响因子：
4.1
通讯作者：
M. Coen;P. Rademacher;W. Zou;M. Scott;P. Ganey;R. Roth;S. Nelson
中科院分区：
文献类型：
--
作者：
M. Coen;P. Rademacher;W. Zou;M. Scott;P. Ganey;R. Roth;S. Nelson
应用基于NMR的代谢组学方法研究了噻吩类化合物噻吩酸（TA）和噻吩酸异构体（TAI）的系统水平代谢效应。代谢组学数据与传统的临床化学和组织病理学分析相结合。由于怀疑免疫介导的肝毒性，TA被从市场上撤下，而TAI是一种内在肝毒素。向Sprague-Dawley大鼠给予等摩尔剂量的TA和TAI，并在给药后2、6和24 h进行采样。组织学分析显示TAI治疗后24小时出现显著肝损伤，血浆丙氨酸氨基转移酶（ALT）活性平行增加。相反，TA与肝损伤的发展或血浆ALT活性的增加无关。在多个时间点生成肝脏提取物、血浆和尿液的高分辨率NMR光谱代谢谱。应用多变量统计工具对代谢特征进行建模，并识别反映TA给药适应性以及TAI诱导的肝毒性发作和进展的歧视性代谢物。TAI在所有时间点均对代谢组产生显著的代谢效应，给药后24 h出现显著的代谢紊乱，这与肝脏病变的组织病理学和临床化学证据相关。TAI诱导的代谢紊乱为亲电活性代谢物的产生和生物能量代谢途径的显著损害提供了证据。TA诱导的早期代谢紊乱在治疗后24小时基本上得到解决，这表明代谢稳态的重建和适应干预的能力，肝亚牛磺酸可能是评估肝脏适应性的一种手段。这种比较代谢组学方法能够区分两种治疗常见的代谢扰动，并将其解释为无毒噻吩诱导的扰动。重要的是，这种方法能够识别TAI或TA治疗特有的时间代谢紊乱，因此与毒性的发展或适应能力相关。这种方法适用于未来的研究，结构相似的化合物，并代表了一个完善的手段，确定生物标志物的毒性。
An NMR-based metabonomic approach was applied to study the systems level metabolic effects of two closely related thiophene compounds, tienilic acid (TA) and tienilic acid isomer (TAI). The metabonomic data were anchored with traditional clinical chemistry and histopathologic analyses. TA was removed from the market as a result of suspected immune-mediated hepatotoxicity, whereas TAI is an intrinsic hepatotoxin. Equimolar doses of TA and TAI were administered to Sprague-Dawley rats, and sampling was conducted at 2, 6, and 24 h post-treatment. Histopathologic analyses revealed development of a significant hepatic lesion 24 h post-TAI treatment with a parallel increase in plasma alanine aminotransferase (ALT) activity. In contrast, TA was not associated with the development of a hepatic lesion or an increase in plasma ALT activity. High-resolution NMR spectral metabolic profiles were generated for liver extracts, plasma, and urine at multiple time points. Multivariate statistical tools were applied to model the metabolic profiles and identify discriminatory metabolites that reflected both the adaptation to TA administration and the onset and progression of TAI-induced hepatotoxicity. TAI was shown to induce marked metabolic effects on the metabolome at all time points, with dramatic metabolic perturbations at 24 h post-treatment correlating with the histopathologic and clinical chemistry evidence of a hepatic lesion. The TAI-induced metabolic perturbations provided evidence for the generation of electrophilic reactive metabolites and a significant impairment of bioenergetic metabolic pathways. TA induced early metabolic perturbations that were largely resolved by 24 h post-treatment, suggesting the reestablishment of metabolic homeostasis and the ability to adapt to the intervention, with hepatic hypotaurine potentially representing a means of assessment of hepatic adaptation. This comparative metabonomic approach enabled the discrimination of metabolic perturbations that were common to both treatments and were interpreted as nontoxic thiophene-induced perturbations. Importantly, this approach enabled the identification of temporal metabolic perturbations that were unique to TAI or TA treatment and hence were of relevance to the development of toxicity or the ability to adapt. This approach is applicable to the future study of pharmacologically and structurally similar compounds and represents a refined means of identification of biomarkers of toxicity.