Metabolomics study of early metabolic changes in hepatic HepaRG cells in response to rosemary diterpenes exposure
Metabolomics study of early metabolic changes in hepatic HepaRG cells in response to rosemary diterpenes exposure
复制标题
DOI：
10.1016/j.aca.2017.12.006
复制
发表时间：
2018-12-11
影响因子：
6.2
通讯作者：
Simo, Carolina
中科院分区：
文献类型：
--
作者：
Acunha, Tanize;Garcia-Canas, Virginia;Simo, Carolina
迷迭香二萜已经证明了多种生物活性，如抗癌、抗炎以及对神经和代谢紊乱的其他有益作用。特别是鼠尾草酸（CA）、鼠尾草醇（CS）和迷迭香醇（RS）二萜在抗癌活性方面显示出有趣的结果。然而，迷迭香二萜在发挥其对癌细胞的抗增殖作用所需浓度时的毒性作用知之甚少。在我们的研究中，CA、CS和RS对两种人结肠癌细胞系（HT-29和HCT116）暴露24小时后的细胞活力表现出浓度依赖性。HT-29细胞株比HCT116细胞株更能抵抗三种二萜的抑制作用。三种二萜中，RS对两种细胞系的作用最强。为了研究CA， CS和RS的肝毒性，将未分化和分化的HepaRG细胞暴露于浓度增加的二萜（从10到100 μ M）中。分化的细胞比未分化的HepaRG更能抵抗三种二萜的毒性活性，这可能与分化的HepaRG细胞比未分化的细胞具有更高的解毒功能有关。通过观察分化后的HepaRG细胞在CA、CS和RS作用下的代谢变化，进一步研究迷迭香酚二萜在分子水平上的作用。一项基于液相和气相色谱联用高分辨率质谱的多平台代谢组学研究显示，当用相同浓度的迷迭香二萜处理HepaRG细胞时，每种二萜对HepaRG细胞的作用不同。RS显示出更大的代谢组改变，其次是CS和CA，这与它们观察到的细胞毒性一致。代谢组学提供了有关迷迭香二萜处理后代谢谱早期事件的宝贵信息。(c) 2018 Elsevier B.V.版权所有
Rosemary diterpenes have demonstrated diverse biological activities, such as anti-cancer, anti-inflammatory, as well as other beneficial effects against neurological and metabolic disorders. In particular, carnosic acid (CA), carnosol (CS) and rosmanol (RS) diterpenes have shown interesting results on anticancer activity. However, little is known about the toxic effects of rosemary diterpenes at the concentrations needed to exert their antiproliferative effect on cancer cells. In our study, CA, CS and RS exhibited a concentration-dependent effect on cell viability of two human colon cancer cell lines (HT-29 and HCT116) after 24 h exposure. HT-29 cell line was more resistant to the inhibitory effect of the three diterpenes than HCT116 cell line. Among the three diterpenes, RS exerted the strongest effect in both cell lines. To investigate the hepatotoxicity of CA, CS and RS, undifferentiated and differentiated HepaRG cells were exposed to increasing concentrations of the diterpenes (from 10 to 100 mu M). Differentiated cells were found to be more resistant to the toxic activity of the three diterpenes than undifferentiated HepaRG, probably related to a higher detoxifying function of differentiated HepaRG cells compared with the undifferentiated cells. The metabolic profiles of differentiated HepaRG cells in response to CA, CS and RS were examined to determine biochemical alterations and deepen the study of the effects of rosemary phenolic diterpenes at molecular level. A multiplatform metabolomics study based on liquid- and gas-chromatography hyphenated to high resolution mass spectrometry revealed that rosemary diterpenes exerted different effects when HepaRG cells were treated with the same concentration of each diterpene. RS revealed a greater metabolome alteration followed by CS and CA, in agreement with their observed cytotoxicity. Metabolomics provided valuable information about early events in the metabolic profiles after the treatment with the investigated diterpenes from rosemary. (c) 2018 Elsevier B.V. All rights reserved.