Dessau Hadar, Harris Talia, de Graaf Robin A, Montrazi Elton T, Allouche-Arnon Hyla, Bar-Shir Amnon
Department of Molecular Chemistry and Materials Science, Weizmann Institute of Science, Rehovot, Israel.
Department of Chemical Research Support, Weizmann Institute of Science, Rehovot, Israel.
Magn Reson Med. 2025 Aug;94(2):521-529. doi: 10.1002/mrm.30531. Epub 2025 Apr 14.
Despite growing evidence of the link between elevated levels of trimethylamine-N-oxide (TMAO) and multiple diseases, there is no method with which to spatially monitor its hepatic formation from the interstitially produced trimethylamine (TMA). This study aimed to develop a deuterium metabolic spectroscopy (DMS) and imaging (DMI) approach to detect the TMA-to-TMAO metabolism in vivo.
The metabolism of H-TMA (TMA-d) to H-TMAO (TMAO-d) in cells overexpressing the hepatic enzyme flavin-dependent monooxygenase 3 (FMO3) was monitored in vitro with H-NMR. Using an ultrahigh-field (15.2T) MRI scanner, the hepatic metabolism of the orally administered TMA-d to TMAO-d was studied in mice with DMS and DMI.
The spectrally resolved H-NMR peaks of intracellularly produced TMAO-d (3.1 ppm) from that of supplemental TMA-d (2.7 ppm) could be detected only in cells that overexpressed FMO3. In vivo, DMS and DMI experiments performed after oral administration of TMA-d revealed the conversion to high TMAO-d levels in the liver of females, which express high levels of FMO3. In contrast, there was no indication of TMAO-d production in the liver of males, in agreement with reports of the role of testosterone in downregulating the expression of FMO3.
This work shows the ability to use H-MR-based methodologies to spatially monitor the TMA-to-TMAO metabolic pathway in vivo, and thus should be explored further to investigate the role of TMAO in diverse pathologies.
尽管越来越多的证据表明氧化三甲胺（TMAO）水平升高与多种疾病之间存在联系，但尚无方法可在空间上监测其由间质产生的三甲胺（TMA）在肝脏中的形成过程。本研究旨在开发一种氘代谢光谱法（DMS）和成像法（DMI），以在体内检测TMA到TMAO的代谢过程。
利用氢核磁共振（H-NMR）在体外监测过表达肝脏酶黄素依赖性单加氧酶3（FMO3）的细胞中H-TMA（TMA-d）到H-TMAO（TMAO-d）的代谢情况。使用超高场（15.2T）磁共振成像（MRI）扫描仪，通过DMS和DMI研究口服TMA-d后小鼠肝脏中TMA-d到TMAO-d的代谢情况。
仅在过表达FMO3的细胞中能够检测到细胞内产生的TMAO-d（3.1 ppm）与补充的TMA-d（2.7 ppm）在光谱上分辨的H-NMR峰。在体内，口服TMA-d后进行的DMS和DMI实验显示，表达高水平FMO3的雌性小鼠肝脏中转化为高TMAO-d水平。相比之下，雄性小鼠肝脏中未显示有TMAO-d产生，这与睾酮下调FMO3表达作用的报道一致。
这项工作表明能够使用基于氢磁共振的方法在体内空间监测TMA到TMAO的代谢途径，因此应进一步探索以研究TMAO在各种病理中的作用。
