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Quantification of the Immunosuppressant Tacrolimus on Dried Blood Spots Using LC-MS/MS
Published on: November 8, 2015
The effect of tacrolimus-induced toxicity on metabolic profiling in target tissues of mice
Dadi Xie1, Jinxiu Guo2, Ruili Dang2
1Tengzhou Central People's Hospital, Tengzhou, 277500, China.
Abstract:
Tacrolimus (Tac) is a common immunosuppressant that used in organ transplantation. However, its therapeutic index is narrow, and it is prone to adverse side effects, along with an increased risk of toxicity, namely, cardio-, nephro-, hepato-, and neurotoxicity. Prior metabolomic investigations involving Tac-driven toxicity primarily focused on changes in individual organs. However, extensive research on multiple matrices is uncommon. Hence, in this research, the authors systemically evaluated Tac-mediated toxicity in major organs, namely, serum, brain, heart, liver, lung, kidney, and intestines, using gas chromatography-mass spectrometry (GC-MS). The authors also employed multivariate analyses, including orthogonal projections to the latent structure (OPLS) and t-test, to screen 8 serum metabolites, namely, D-proline, glycerol, D-fructose, D-glucitol, sulfurous acid, 1-monopalmitin (MG (16:0/0:0/0:0)), glycerol monostearate (MG (0:0/18:0/0:0)), and cholesterol. Metabolic changes within the brain involved alterations in the levels of butanamide, tartronic acid, aminomalonic acid, scyllo-inositol, dihydromorphine, myo-inositol, and 11-octadecenoic acid. Within the heart, the acetone and D-fructose metabolites were altered. In the liver, D-glucitol, L-sorbose, palmitic acid, myo-inositol, and uridine were altered. In the lung, L-lactic acid, L-5-oxoproline, L-threonine, phosphoric acid, phosphorylethanolamine, D-allose, and cholesterol were altered. Lastly, in the kidney, L-valine and D-glucose were altered. Our findings will provide a systematic evaluation of the metabolic alterations in target organs within a Tac-driven toxicity mouse model.
Insights
Tacrolimus (Tac) toxicity impacts multiple organs, causing significant metabolic changes across serum, brain, heart, liver, lung, and kidney. This study provides a comprehensive metabolomic analysis of Tac-induced damage in various tissues.
Area of Science:
- Biochemistry
- Toxicology
- Pharmacology
Background:
- Tacrolimus (Tac) is a vital immunosuppressant in organ transplantation.
- Tacrolimus exhibits a narrow therapeutic index, leading to significant cardio-, nephro-, hepato-, and neurotoxicity.
- Previous metabolomic studies on Tac toxicity focused on single organs, limiting a holistic understanding.
Purpose of the Study:
- To systematically evaluate Tac-mediated toxicity across multiple organs using a metabolomic approach.
- To identify specific metabolic alterations in serum, brain, heart, liver, lung, and kidney following Tac administration.
- To establish a comprehensive profile of Tac-induced metabolic disturbances in a mouse model.
Main Methods:
- Utilized gas chromatography-mass spectrometry (GC-MS) for comprehensive metabolomic profiling.
- Employed multivariate statistical analyses, including orthogonal projections to the latent structure (OPLS) and t-tests.
- Analyzed metabolic changes in serum, brain, heart, liver, lung, and kidney tissues.
Main Results:
- Identified distinct sets of altered metabolites in each analyzed organ.
- Serum metabolites such as D-proline and cholesterol were affected.
- Brain metabolism showed alterations in butanamide and myo-inositol levels.
- Heart, liver, lung, and kidney also exhibited unique metabolic signatures of Tac toxicity, including changes in D-fructose, palmitic acid, L-lactic acid, and L-valine, respectively.
Conclusions:
- This study presents a systematic, multi-organ metabolomic evaluation of Tacrolimus toxicity.
- Findings reveal specific metabolic fingerprints of Tac-induced damage in various organs.
- Provides a foundational dataset for understanding Tacrolimus's systemic toxic effects and potential therapeutic strategies.
