1 Division of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman 11942, Jordan.
2 Department of Chemistry and Biochemistry, Concordia University, 7141 Sherbrook Street West, Montréal, QC H4B 1R6, Canada.
3 Department of Comparative Medicine, King Faisal Specialist Hospital and Research Center (KFSHRC), Riyadh 11461, Saudi Arabia.
4 Department of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada.
5 Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Centre, Riyadh 11461, Saudi Arabia.
6 Department of Pathology, Clinical Biochemistry Unit, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia.
7 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
8 Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia.
9 Department of Chemistry, College of Medicine, Memorial University of Newfoundland, St. John's, NL A1B 3V6, Canada.

Dexamethasone (Dex) is a synthetic glucocorticoid (GC) drug commonly used clinically for the treatment of several inflammatory and immune-mediated diseases. Despite its broad range of indications, the long-term use of Dex is known to be associated with specific abnormalities in several tissues and organs. In this study, the metabolomic effects on five different organs induced by the chronic administration of Dex in the Sprague-Dawley rat model were investigated using the chemical isotope labeling liquid chromatography-mass spectrometry (CIL LC-MS) platform, which targets the amine/phenol submetabolomes. Compared to controls, a prolonged intake of Dex resulted in significant perturbations in the levels of 492, 442, 300, 186, and 105 metabolites in the brain, skeletal muscle, liver, kidney, and heart tissues, respectively. The positively identified metabolites were mapped to diverse molecular pathways in different organs. In the brain, perturbations in protein biosynthesis, amino acid metabolism, and monoamine neurotransmitter synthesis were identified, while in the heart, pyrimidine metabolism and branched amino acid biosynthesis were the most significantly impaired pathways. In the kidney, several amino acid pathways were dysregulated, which reflected impairments in several biological functions, including gluconeogenesis and ureagenesis. Beta-alanine metabolism and uridine homeostasis were profoundly affected in liver tissues, whereas alterations of glutathione, arginine, glutamine, and nitrogen metabolism pointed to the modulation of muscle metabolism and disturbances in energy production and muscle mass in skeletal muscle. The differential expression of multiple dipeptides was most significant in the liver (down-regulated), brain (up-regulation), and kidney tissues, but not in the heart or skeletal muscle tissues. The identification of clinically relevant pathways provides holistic insights into the tissue molecular responses induced by Dex and understanding of the underlying mechanisms associated with their side effects. Our data suggest a potential role for glutathione supplementation and dipeptide modulators as novel therapeutic interventions to mitigate the side effects induced by Dex therapy.