Linezolid Inhibited Synthesis of ATP in Mitochondria: Based on GC-MS Metabolomics and HPLC Method

Area of Science:

• Pharmacology
• Toxicology
• Biochemistry

Background:

• Linezolid is crucial for treating serious infections caused by multidrug-resistant gram-positive pathogens.
• However, linezolid use is associated with severe adverse reactions, including thrombocytopenia, anemia, optic neuropathy, and serotonin syndrome.
• Understanding the mechanisms behind linezolid's toxicity is essential for patient safety.

Purpose of the Study:

• To investigate the toxicity of linezolid in Sprague-Dawley rats.
• To correlate linezolid serum concentration with observed metabolic changes and cellular effects.
• To identify potential biochemical pathways affected by linezolid treatment.

Main Methods:

• Twenty-four rats were divided into control, low-dose (60 mg/kg/day), and high-dose (120 mg/kg/day) linezolid groups for 7 days.
• Serum linezolid concentrations were measured using high-performance liquid chromatography (HPLC).
• Metabolic profiles were analyzed by gas chromatography-mass spectrometry (GC-MS), and adenosine triphosphate (ATP) levels in HepG2-C3A cells were determined by HPLC.

Main Results:

• Significant alterations in nine metabolites were observed in both low- and high-dose groups compared to controls (P<0.05).
• Trimethyl phosphate emerged as a key indicator of metabolic change.
• Levels of various fatty acids and cholest-5-ene decreased, while d-glucose showed a slight increase in the low-dose group. ATP concentration was reduced in linezolid-treated HepG2-C3A cells.

Conclusions:

• Linezolid toxicity is directly related to its serum concentration.
• The findings suggest that linezolid may inhibit adenosine triphosphate (ATP) synthesis and fatty acid synthesis pathways.
• Further research is warranted to elucidate the precise mechanisms of linezolid-induced toxicity.