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Systematic Evaluations of Doxorubicin-Induced Toxicity in Rats Based on Metabolomics
Chunmei Geng1, Changmeng Cui2, Changshui Wang2
1Department of Pharmacy, Jining No 1 People's Hospital, Jining Medical University, Jining 272000, China.
Abstract:
Doxorubicin (DOX) is widely used to treat solid tumors, but its use is limited by its severe cardiotoxicity, nephrotoxicity, hepatotoxicity, and neurotoxicity. Metabolomic studies on DOX-induced toxicity are mainly focused on alterations in the heart and kidney, but systematic research on multiple matrices (serum, heart, liver, brain, and kidney) is rare. Thus, in our study, gas chromatography-mass spectrometry analysis of main targeted tissues (serum, heart, liver, brain, and kidney) was used to systemically evaluate the toxicity of DOX. Multivariate analyses, including orthogonal projections to the latent structure and t-test, revealed 21 metabolites in the serum, including cholesterol, d-glucose, d-lactic acid, glycine, l-alanine, l-glutamic acid, l-isoleucine, l-leucine, l-proline, l-serine, l-tryptophan, l-tyrosine, l-valine, MG (0:0/18:0/0:0), MG (16:0/0:0/0:0), N-methylphenylethanolamine, oleamide, palmitic acid, pyroglutamic acid, stearic acid, and urea. In the heart, perturbed metabolites included 3-methyl-1-pentanol, cholesterol, d-glucose, d-lactic acid, glycerol, glycine, l-alanine, l-valine, MG (16:0/0:0/0:0), palmitic acid, phenol, propanoic acid, and stearic acid. For the liver, DOX exposure caused alterations of acetamide, acetic acid, d-glucose, glycerol, l-threonine, palmitic acid, palmitoleic acid, stearic acid, and urea. In the brain, metabolic changes involved 2-butanol, carbamic acid, cholesterol, desmosterol, d-lactic acid, l-valine, MG (16:0/0:0/0:0), palmitic acid, and stearic acid. In the kidney, disturbed metabolites were involved in cholesterol, glycerol, glycine, l-alanine, MG (0:0/18:0/0:0), MG (16:0/0:0/0:0), and squalene. Complementary evidence by multiple matrices revealed disturbed pathways concerning amino acid metabolism, energy metabolism, and lipid metabolism. Our results may help to systematically elucidate the metabolic changes of DOX-induced toxicity and clarify the underlying mechanisms.
Insights
This study systematically evaluated Doxorubicin (DOX) toxicity across multiple tissues using metabolomics. Findings reveal significant metabolic alterations in amino acid, energy, and lipid pathways, aiding in understanding DOX-induced toxicity mechanisms.
Area of Science:
- Biochemistry
- Toxicology
- Metabolomics
Background:
- Doxorubicin (DOX) is a vital chemotherapy drug for solid tumors.
- DOX use is limited by severe cardiotoxicity, nephrotoxicity, hepatotoxicity, and neurotoxicity.
- Previous metabolomic studies on DOX toxicity primarily focused on the heart and kidney, lacking a multi-matrix approach.
Purpose of the Study:
- To systematically evaluate the toxicity of Doxorubicin (DOX) across multiple biological matrices.
- To identify specific metabolic alterations induced by DOX in serum, heart, liver, brain, and kidney.
- To elucidate the underlying mechanisms of DOX-induced toxicity through comprehensive metabolomic analysis.
Main Methods:
- Gas chromatography-mass spectrometry (GC-MS) analysis was performed on serum, heart, liver, brain, and kidney samples.
- Multivariate statistical analyses, including orthogonal projections to latent structures (OPLS) and t-tests, were employed.
- Metabolite profiles were analyzed to identify significant changes in response to DOX exposure.
Main Results:
- Significant alterations in 21 metabolites were identified in serum, including cholesterol, glucose, amino acids, and fatty acids.
- Perturbed metabolites were also detected in the heart, liver, brain, and kidney, affecting various metabolic pathways.
- Key affected pathways included amino acid metabolism, energy metabolism, and lipid metabolism across the analyzed matrices.
Conclusions:
- This study provides a comprehensive, multi-matrix metabolomic profile of Doxorubicin-induced toxicity.
- The findings highlight significant disturbances in amino acid, energy, and lipid metabolism.
- This research contributes to a deeper understanding of the mechanisms underlying DOX toxicity, potentially informing strategies to mitigate its adverse effects.
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