AUTHOR=Zhao Tongfeng , Zhao Yaxin , Chen Haotian , Sun Wenxue , Guan Yun 

TITLE=A GC–MS-based untargeted metabolomics approach for comprehensive metabolic profiling of mycophenolate mofetil-induced toxicity in mice

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=11

YEAR=2024

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2024.1332090

DOI=10.3389/fmolb.2024.1332090

ISSN=2296-889X

ABSTRACT=<p><bold>Background:</bold> Mycophenolate mofetil (MMF), the morpholinoethyl ester of mycophenolic acid, is widely used for maintenance immunosuppression in transplantation. The gastrointestinal toxicity of MMF has been widely uncovered. However, the comprehensive metabolic analysis of MMF-induced toxicity is lacking. This study is aimed to ascertain the metabolic changes after MMF administration in mice.</p><p><bold>Methods:</bold> A total of 700 mg MMF was dissolved in 7 mL dimethyl sulfoxide (DMSO), and then 0.5 mL of mixture was diluted with 4.5 mL of saline (100 mg/kg). Mice in the treatment group (<italic>n</italic> = 9) were given MMF (0.1 mL/10 g) each day via intraperitoneal injection lasting for 2 weeks, while those in the control group (<italic>n</italic> = 9) received the same amount of blank solvent (DMSO: saline = 1:9). Gas chromatography-mass spectrometry was utilized to identify the metabolic profiling in serum samples and multiple organ tissues of mice. The potential metabolites were identified using orthogonal partial least squares discrimination analysis. Meanwhile, we used the MetaboAnalyst 5.0 (<ext-link ext-link-type="uri" xlink:href="http://www.metaboanalyst.ca" xmlns:xlink="http://www.w3.org/1999/xlink">http://www.metaboanalyst.ca</ext-link>) and Kyoto Encyclopedia of Genes and Genomes database (<ext-link ext-link-type="uri" xlink:href="http://www.kegg.jp" xmlns:xlink="http://www.w3.org/1999/xlink">http://www.kegg.jp</ext-link>) to depict the metabolic pathways. The percentages of lymphocytes in spleens were assessed by multiparameter flow cytometry analysis.</p><p><bold>Results:</bold> Compared to the control group, we observed that MMF treatment induced differential expression of metabolites in the intestine, hippocampus, lung, liver, kidney, heart, serum, and cortex tissues. Subsequently, we demonstrated that multiple amino acids metabolism and fatty acids biosynthesis were disrupted following MMF treatment. Additionally, MMF challenge dramatically increased CD4<sup>+</sup> T cell percentages but had no significant influences on other types of lymphocytes.</p><p><bold>Conclusion:</bold> MMF can affect the metabolism in various organs and serum in mice. These data may provide preliminary judgement for MMF-induced toxicity and understand the metabolic mechanism of MMF more comprehensively.</p>