Detection of hepatotoxicity potential with metabolite profiling (metabolomics) of rat plasma
Detection of hepatotoxicity potential with metabolite profiling (metabolomics) of rat plasma
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DOI：
10.1016/j.toxlet.2014.07.021
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发表时间：
2014-11-04
影响因子：
3.5
通讯作者：
Kamp, H.
中科院分区：
文献类型：
--
作者：
Mattes, W.;Davis, K.;Kamp, H.
虽然在药物安全性评估研究中用于检测肝毒性的常规参数通常是信息性的，但仍然需要能够在较低剂量和/或较早时间点检测肝毒性潜力的参数。先前的工作表明，代谢物分析（代谢组学/代谢组学）可以检测到在用常规参数监测时不会引起肝毒性的剂量下用多柔比星处理的大鼠中的潜在肝毒性信号。目前的研究将这一观察结果扩展到这样的问题，即在用可以引起人类肝毒性的化合物处理的大鼠中是否可以检测到这样的信号（即，药物诱导的肝损伤，DILI），但尚未报道在大鼠中发生。根据已知的DILI潜力选择了9种化合物，选择了6种其他化合物作为DILI潜力阴性。大鼠血浆代谢物谱数据库MetaMape（R）Tox（由metanomics GmbH和BASF SE开发）用于许多已知毒性的代谢物谱和作用模式（MoA）代谢物特征。9种具有DILI潜力的化合物中有8种引起的代谢产物谱与各种大鼠肝毒性的MoA模式相匹配，包括胆汁淤积、氧化应激、对乙酰氨基酚型毒性和过氧化物酶体增殖。相比之下，六种非DILI化合物中只有一种显示出与大鼠肝毒性的弱匹配。这些结果表明，代谢物谱分析可能确实有希望检测用具有DILI潜力的化合物处理的大鼠中的肝毒性信号。(C)2014爱思唯尔爱尔兰有限公司版权所有。
While conventional parameters used to detect hepatotoxicity in drug safety assessment studies are generally informative, the need remains for parameters that can detect the potential for hepatotoxicity at lower doses and/or at earlier time points. Previous work has shown that metabolite profiling (metabonomics/metabolomics) can detect signals of potential hepatotoxicity in rats treated with doxorubicin at doses that do not elicit hepatotoxicity as monitored with conventional parameters. The current study extended this observation to the question of whether such signals could be detected in rats treated with compounds that can elicit hepatotoxicity in humans (i.e., drug-induced liver injury, DILI) but have not been reported to do so in rats. Nine compounds were selected on the basis of their known DILI potential, with six other compounds chosen as negative for DILI potential. A database of rat plasma metabolite profiles, MetaMape (R) Tox (developed by metanomics GmbH and BASF SE) was used for both metabolite profiles and mode of action (MoA) metabolite signatures for a number of known toxicities. Eight of the nine compounds with DILI potential elicited metabolite profiles that matched with MoA patterns of various rat liver toxicities, including cholestasis, oxidative stress, acetaminophen-type toxicity and peroxisome proliferation. By contrast, only one of the six non-DILI compounds showed a weak match with rat liver toxicity. These results suggest that metabolite profiling may indeed have promise to detect signals of hepatotoxicity in rats treated with compounds having DILI potential. (C) 2014 Elsevier Ireland Ltd. All rights reserved.