Noninvasive in vivo magnetic resonance measures of glutathione synthesis in human and rat liver as an oxidative stress biomarker.
Noninvasive in vivo magnetic resonance measures of glutathione synthesis in human and rat liver as an oxidative stress biomarker.
复制标题
DOI：
10.1002/hep.26925
复制
发表时间：
2014-06
期刊：
影响因子：
13.5
通讯作者：
Thelwall, Peter E.
中科院分区：
文献类型：
--
作者：
Skamarauskas, John T.;Oakley, Fiona;Smith, Fiona E.;Bawn, Carlo;Dunn, Michael;Vidler, Daniel S.;Clemence, Matthew;Blain, Peter G.;Taylor, Roy;Gamcsik, Michael P.;Thelwall, Peter E.
氧化应激（OS）在肝脏疾病的进展和毒性外源性物质对肝脏的损害中起着核心作用。我们已经开发了通过测量谷胱甘肽（GSH）合成途径的通量来非侵入性评估肝脏OS防御的方法。13 C标记的GSH是内源性产生的，并在[2- 13 C]-甘氨酸给药后通过体内磁共振检测。我们报告了有史以来第一次成功的人类演示这种方法以及临床前研究表明扰动GSH代谢的模型中的急性和慢性OS. Human研究采用口服给药[2- 13 C]-甘氨酸和13 C光谱的3 T临床磁共振（MR）成像扫描仪，并证明了检测和定量标记甘氨酸摄入后内源性产生的13 C-GSH。血浆分析表明，甘氨酸13 C部分富集在6小时摄入期间达到稳态。肝脏13 C标记GSH的平均合成速率为0.32 ± 0.18 mmol/kg/h。急性OS和非酒精性脂肪性肝炎（NASH）的临床前模型分别包括CCl 4处理和高脂肪、高碳水化合物饮食喂养的Sprague-Dawley大鼠，使用静脉注射[2- 13 C]-甘氨酸并在7 T临床前MR系统上观察13 C标记代谢。临床前研究表明，在由CCl 4给药引起的急性损伤后12小时，GSH含量升高54%，通过GSH合成途径的通量增加31%，以及GSH含量降低23%，NASH模型中存在早期脂肪性肝炎的证据。结论：我们的数据表明，在体内13 C-标记和检测GSH作为组织OS防御的生物标志物，检测慢性和急性OS损伤。该方法适用于随时间推移的疾病状态下肝脏OS的临床研究以及监测治疗干预的效果。
Oxidative stress (OS) plays a central role in the progression of liver disease and in damage to liver by toxic xenobiotics. We have developed methods for noninvasive assessment of hepatic OS defenses by measuring flux through the glutathione (GSH) synthesis pathway. 13C-labeled GSH is endogenously produced and detected by in vivo magnetic resonance after administration of [2-13C]-glycine. We report on a successful first-ever human demonstration of this approach as well as preclinical studies demonstrating perturbed GSH metabolism in models of acute and chronic OS. Human studies employed oral administration of [2-13C]-glycine and 13C spectroscopy on a 3T clinical magnetic resonance (MR) imaging scanner and demonstrated detection and quantification of endogenously produced 13C-GSH after labeled glycine ingestion. Plasma analysis demonstrated that glycine 13C fractional enrichment achieved steady state during the 6-hour ingestion period. Mean rate of synthesis of hepatic 13C-labeled GSH was 0.32 ± 0.18 mmole/kg/hour. Preclinical models of acute OS and nonalcoholic steatohepatitis (NASH) comprised CCl4-treated and high-fat, high-carbohydrate diet-fed Sprague-Dawley rats, respectively, using intravenous administration of [2-13C]-glycine and observation of 13C-label metabolism on a 7T preclinical MR system. Preclinical studies demonstrated a 54% elevation of GSH content and a 31% increase in flux through the GSH synthesis pathway at 12 hours after acute insult caused by CCl4 administration, as well as a 23% decrease in GSH content and evidence of early steatohepatitis in the model of NASH. Conclusion: Our data demonstrate in vivo 13C-labeling and detection of GSH as a biomarker of tissue OS defenses, detecting chronic and acute OS insults. The methods are applicable to clinical research studies of hepatic OS in disease states over time as well as monitoring effects of therapeutic interventions.
登录
查看更多内容
影响因子：
2.9
作者：
Thelwall, Peter E.;Simpson, Nicholas E.;Rabbani, Zahid N.;Clark, M. Daniel;Pourdeyhimi, Roxana;Macdonald, Jeffrey M.;Blackband, Stephen J.;Gamcsik, Michael P.
通讯作者：
Gamcsik, Michael P.
影响因子：
5
作者：
Comporti, M;Arezzini, B;Gardi, C
通讯作者：
Gardi, C
影响因子：
3.3
作者：
Terpstra, Melissa;Marjanska, Malgorzata;Gruetter, Rolf
通讯作者：
Gruetter, Rolf
影响因子：
3.3
作者：
Macdonald, JM;Schmidlin, O;James, TL
通讯作者：
James, TL
影响因子：
2.9
作者：
Iuliano, L;Micheletta, F;Diczfalusy, U
通讯作者：
Diczfalusy, U