Endogenous and xenobiotic metabolite profiling of liver extracts from SCID and chimeric humanized mice following repeated oral administration of troglitazone
Endogenous and xenobiotic metabolite profiling of liver extracts from SCID and chimeric humanized mice following repeated oral administration of troglitazone
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DOI：
10.3109/00498254.2013.867463
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发表时间：
2014-02-01
期刊：
影响因子：
1.8
通讯作者：
Wilson, Ian D.
中科院分区：
文献类型：
--
作者：
Barnes, Alan J.;Baker, David R.;Wilson, Ian D.
1.通过非靶向和靶向液质联用(LC-MS)和基于非靶向H-1核磁共振谱的代谢物图谱相结合的代谢组学分析，对给予曲格列酮0、300和600 mg/kg/d的对照(SCID)和嵌合人源化(PXB)小鼠的水提取物(AQ)和有机肝提取物(PXB)进行了连续7天的代谢组学分析。AQ肝脏提取物的LC-MS分析显示，与SCID，小鼠相比，PXB的曲格列酮代谢物更接近人类。LC-MS检测到与SCID小鼠肝脏提取物相比，服用PXB的小鼠内源性代谢物，特别是脂质种类的差异，包括三酰甘油和1-烷基，2-烷基甘油磷酸盐的升高，以及PXB的二酰基甘油磷胆碱和1-烷基，2-脂基甘油磷胆碱的降低。在给药后，观察到两种类型的小鼠各种不饱和脂肪酸离子的相对比例发生了变化，其中一些是PXB或SCID小鼠所特有的。H-1核磁共振波谱显示，与SCID小鼠相比，AQ PXB小鼠肝脏提取物中的肌苷、富马酸、肌酸、天冬氨酸、三甲胺N-氧化物、甘油磷胆碱、磷胆碱、胆碱、谷氨酰胺、谷氨酸、醋酸盐、丙氨酸和乳酸的含量增加，组氨酸、糖原、α-和β-葡萄糖、牛磺酸和谷胱甘肽的含量降低。服用曲格列酮的PXB小鼠尿嘧啶和酪氨酸浓度升高。因此，代谢组学分析显示人源化和SCID小鼠之间存在明显的差异，包括在给药曲格列酮之后。
1. Metabonomic analysis, via a combination of untargeted and targeted liquid chromatography-mass spectrometry (LC-MS) and untargeted H-1 NMR spectroscopy-based metabolite profiling, was performed on aqueous (AQ) and organic liver extracts from control (SCID) and chimeric humanized (PXB) mice dosed with troglitazone at 0, 300 and 600 mg/kg/day for seven days.2. LC-MS analysis of AQ liver extracts showed a more "human-like" profile for troglitazone metabolites for PXB, compared with SCID, mice.3. LC-MS detected differences in endogenous metabolites, particularly lipid species in dosed mice, including elevated triacylglycerols and 1-alkyl, 2-acylglycerophosphates as well as lowered diacylglycerophosphocholines and 1-alkyl, 2-acylglycerophosphocholines for PXB compared with SCID mouse liver extracts. Following drug administration changes in the relative proportions of the ions for various unsaturated fatty acids were observed for both types of mouse, some of which were specific to PXB or SCID mice.4. H-1 NMR spectroscopy revealed that AQ PXB mouse liver extracts had elevated amounts of inosine, fumarate, creatine, aspartate, trimethylamine N-oxide, glycerophosphocholine, phosphocholine, choline, glutamine, glutamate, acetate, alanine and lactate relative to SCID mice and decreased histidine, glycogen, alpha- and beta-glucose, taurine, and glutathione. Increased uracil and tyrosine concentrations were detected for PXB mice on troglitazone administration.5. Metabonomic profiling thus showed clear differences between humanized and SCID mice, including after administration of troglitazone.