Comprehensive metabolomics study identifies SN-38 organ specific toxicity in mice

Area of Science:

• Pharmacology and Toxicology
• Metabolomics
• Cancer Therapeutics

Background:

• SN-38 (7-ethyl-10-hydroxycamptothecin) is the active metabolite of irinotecan (CPT-11), a chemotherapy drug used for solid tumors.
• Irinotecan treatment is linked to severe adverse effects, including nausea, vomiting, diarrhea, and liver damage, but the underlying biochemical mechanisms are not fully understood.
• Understanding SN-38's toxicity is crucial for developing safer drug delivery systems and improving clinical outcomes for cancer patients.

Purpose of the Study:

• To investigate the multi-organ toxic mechanisms of SN-38 using an untargeted metabolomics approach.
• To identify specific metabolic pathways affected by SN-38 exposure in various tissues.
• To provide insights into the biochemical basis of SN-38's side effects for enhanced clinical application of irinotecan-based therapies.

Main Methods:

• Male mice were administered SN-38 (20 mg/kg/day intraperitoneally) or a control solvent.
• Untargeted metabolomics analysis was performed on lung, heart, stomach, blood, spleen, intestine, liver, and kidney tissues using gas chromatography-mass spectrometry (GC-MS).
• KEGG pathway enrichment analysis was employed to identify significantly altered metabolic pathways.

Main Results:

• Significant metabolic disturbances were detected in all analyzed tissues following SN-38 exposure.
• A substantial number of differential metabolites were identified across organs: 24 in lungs, 15 in heart, 12 in stomach, 21 in blood, 35 in spleen, 26 in intestine, 18 in liver, and 28 in kidneys.
• KEGG pathway analysis revealed significant alterations in purine, pyrimidine, amino acid, and glyceric acid metabolism, indicating disruptions in protein synthesis, cellular homeostasis, energy metabolism, and antioxidant defenses.

Conclusions:

• This study provides the first comprehensive metabolomic characterization of SN-38's multi-organ toxicity.
• SN-38 significantly disrupts fundamental metabolic pathways across multiple organs, contributing to its adverse effects.
• The findings highlight the importance of considering metabolic perturbations in the development of irinotecan-based cancer treatments and drug delivery systems.