Metabolic Profiling to Identify Potential Serum Biomarkers for Gastric Ulceration Induced by Nonsteroid Anti-Inflammatory Drugs

Abstract

Nonsteroid anti-inflammatory drugs (NSAIDs) are among the most frequently prescribed drugs currently available. The most frequently reported serious side effects associated with NSAIDs are gastric mucosal ulceration and gastric hemorrhage. Presently, these side effects are only detectable by endoscopy, however, and no biomarkers have yet been identified. The ability to identify serum biomarkers would likely improve the safety of NSAID use. In this study we performed capillary electrophoresis-mass spectrometry (CE-MS)-based metabolomic profiling in stomach extract and serum from rats administered NSAIDs. Results showed drug-induced decreases in levels of citrate, cis-aconitate, succinate, 3-hydroxy butanoic acid, o-acetyl carnitine, proline, and hydroxyproline. We consider that these changes are due to NSAID-induced depression of mitochondrial function and activation of collagenase by lesions in the stomach. In addition, four of these changes in metabolite levels in the stomach were significantly correlated with changes in the serum. While further study is needed to clarify the mechanism of change in the level of these biomarkers, limitation of indications, and extrapolation to humans, these new serum biomarker candidates of gastric injury may be useful in the monitoring of NSAID-induced tissue damage.

Hydroxyproline, a Serum Biomarker Candidate for Gastric Ulcer in Rats: A Comparison Study of Metabolic Analysis of Gastric Ulcer Models Induced by Ethanol, Stress, and Aspirin

“…We previously reported five biomarker candidates in serum that predict gastric injury induced by NSAIDs in rats 5. We also reported that the decrease in hydroxyproline in stomach induced by aspirin recovered to the control level on co-administration with omeprazole and famotidine.…”

“…System control and data acquisition were done using the Agilent G2201AA ChemStation software for CE and Analyst QS software for TOF–MS. Annotation tables were generated by the same method used in our previous study 5,6…”

CE-MS in Metabolomics

“…They have serious side effects of gastric mucosal ulceration and gastric hemorrhage. Takeuchi et al applied a shotgun approach based on CE-TOFMS profiles of endogenous metabolites to identify new biomarkers of NSAID-induced gastric injury in rat stomach tissue [59]. The levels of citric acid, cis-aconitic acid, succinic acid, 3-hydroxybutanoic acid, o-acetyl carnitine, proline, and hydroxyproline were decreased in the NSAID stomach tissue compared with the healthy tissue.…”

Metabolomics of Neurodegenerative Diseases

“…Effective sample preparation with minimal sample loss is particularly important in the study of the metabolomics of neurodegenerative disease where CSF samples may be limited to only a few milliliters. To address these challenges, methods such as solid-phase microextraction have been developed (Cudjoe, Bojko, de Lannoy, Saldivia, & Pawliszyn, 2013) as well as ion mobility spectrometry (Castro-Perez et al, 2011;Sowell et al, 2004;Zinnel, Pai, & Russell, 2012) and capillary electrophoresis-mass spectrometry (Nevedomskaya et al, 2010;Takeuchi et al, 2013).…”