ABSTRACT
Nuclear magnetic resonance (NMR)-based metabolomic profiling identified urinary 1- and 3-methylhistidine (1- and 3-MH) as potential biomarkers of skeletal muscle toxicity in Sprague-Dawley rats following 7 and 14 daily doses of 0.5 or 1mg/kg cerivastatin. These metabolites were highly correlated to sex-, dose- and time-dependent development of cerivastatin-induced myotoxicity. Subsequently, the distribution and concentration of 1- and 3-MH were quantified in 18 tissues by gas chromatography-mass spectrometry. The methylhistidine isomers were most abundant in skeletal muscle with no fiber or sex differences observed; however, 3-MH was also present in cardiac and smooth muscle. In a second study, rats receiving 14 daily doses of 1mg/kg cerivastatin (a myotoxic dose) had 6- and 2-fold elevations in 1- and 3-MH in urine and had 11- and 3-fold increases in 1- and 3-MH in serum, respectively. Selectivity of these potential biomarkers was tested by dosing rats with the cardiotoxicant isoproterenol (0.5mg/kg), and a 2-fold decrease in urinary 1- and 3-MH was observed and attributed to the anabolic effect on skeletal muscle. These findings indicate that 1- and 3-MH may be useful urine and serum biomarkers of drug-induced skeletal muscle toxicity and hypertrophy in the rat, and further investigation into their use and limitations is warranted.
Subject(s)
Magnetic Resonance Spectroscopy/methods , Metabolomics/methods , Methylhistidines/metabolism , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Animals , Biomarkers/metabolism , Biomarkers/urine , Creatine/metabolism , Creatine/urine , Dose-Response Relationship, Drug , Female , Male , Methylhistidines/pharmacokinetics , Methylhistidines/urine , Muscular Diseases/chemically induced , Muscular Diseases/metabolism , Muscular Diseases/urine , Pyridines/toxicity , Rats , Rats, Sprague-Dawley , Time FactorsSubject(s)
Biomarkers , Drug-Related Side Effects and Adverse Reactions , Endothelium, Vascular/drug effects , Vascular Diseases/chemically induced , Animals , Computational Biology , Drug Evaluation, Preclinical , Endothelium, Vascular/pathology , Flow Cytometry , Genomics , Humans , Proteomics , Vascular Diseases/metabolism , Vasculitis/chemically induced , Vasculitis/metabolismABSTRACT
OBJECTIVE: To investigate the way how sodium salicylate affects cochlear function and discuss its possible mechanism. METHOD: Sodium salicylate was perfused through guinea pig cochlea. The thresholds and input-output (I/O) functions of compound action potential (CAP) and summating potential (SP) were monitored during the perfusion. RESULT: Sodium salicylate caused a significant change of CAP and SP threshold as well as I/O curve. The relationship between CAP and SP threshold change at 10 kHz during perfusion with 10 mmol/L salicylate tends to be 1:1. CONCLUSION: Outer hair cells are most likely to be the sites of action of sodium salicylate and this action on the outer hair cell active process might lead to its ototoxicity.