Effects of acute systematic hypoxia on human urinary metabolites using LC-MS-based metabolomics.

The metabolic variability and response to acute systematic hypoxia have been characterized by the high resolution of liquid chromatography/time-of-flight/mass spectrometry (LC-TOF/MS) in this study. Specifically, we compared the urinary metabolic profiles of six healthy sedentary men under normoxia (21% O2) with acute systematic hypoxic conditions of 12% (equivalent to about 4500 m in altitude) and 15% O2 (equivalent to about 3000 m in altitude) for 2 h in a normobaric hypoxia chamber. A clear separation of dose-dependent responses was visualized by Partial Least Squares Discriminant Analysis (PLS-DA) between normoxic and hypoxic conditions. Over one thousand features were found in this study, about 10% of which showed significant change from hypoxia treatment and 26 metabolites were identified; however, there is great variability in metabolite concentrations among the 6 subjects, which reflects the diversity of human systems. Within the variability, we found that 1-methyladenosine and 5-methylthioadenosine are conspicuously upregulated; on the other hand, 3-inodoleacetic acid and L-glutamic acid were downregulated. The increase in purine metabolic products (uric acid, xanthine, and hypoxathine) results from hypoxia; this increase can be used as a marker for the hypoxic condition. 1-Methyladenosine was also highly upregulated from MH to SH and may be a very sensitive biomarker that reflects cellular hypoxia, due to its potential connection to HIF-1. The increase of free carnitine and acetyl carnitines, on the other hand, signals a change in the pathway of energy, or lipid, metabolism.