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Identification of Human Plasma Metabolites Exhibiting Time-of-Day Variation Using an Untargeted Liquid Chromatography-Mass Spectrometry Metabolomic Approach.

Ang, JE, Revell, V, Mann, A, Mäntele, S, Otway, DT, Johnston, JD, Thumser, AE, Skene, DJ and Raynaud, F (2012) Identification of Human Plasma Metabolites Exhibiting Time-of-Day Variation Using an Untargeted Liquid Chromatography-Mass Spectrometry Metabolomic Approach. Chronobiol Int, 29 (7). 868 - 881. ISSN 0742-0528

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Although daily rhythms regulate multiple aspects of human physiology, rhythmic control of the metabolome remains poorly understood. The primary objective of this proof-of-concept study was identification of metabolites in human plasma that exhibit significant 24-h variation. This was assessed via an untargeted metabolomic approach using liquid chromatography-mass spectrometry (LC-MS). Eight lean, healthy, and unmedicated men, mean age 53.6 (SD ± 6.0) yrs, maintained a fixed sleep/wake schedule and dietary regime for 1 wk at home prior to an adaptation night and followed by a 25-h experimental session in the laboratory where the light/dark cycle, sleep/wake, posture, and calorific intake were strictly controlled. Plasma samples from each individual at selected time points were prepared using liquid-phase extraction followed by reverse-phase LC coupled to quadrupole time-of-flight MS analysis in positive ionization mode. Time-of-day variation in the metabolites was screened for using orthogonal partial least square discrimination between selected time points of 10:00 vs. 22:00 h, 16:00 vs. 04:00 h, and 07:00 (d 1) vs. 16:00 h, as well as repeated-measures analysis of variance with time as an independent variable. Subsequently, cosinor analysis was performed on all the sampled time points across the 24-h day to assess for significant daily variation. In this study, analytical variability, assessed using known internal standards, was low with coefficients of variation <10%. A total of 1069 metabolite features were detected and 203 (19%) showed significant time-of-day variation. Of these, 34 metabolites were identified using a combination of accurate mass, tandem MS, and online database searches. These metabolites include corticosteroids, bilirubin, amino acids, acylcarnitines, and phospholipids; of note, the magnitude of the 24-h variation of these identified metabolites was large, with the mean ratio of oscillation range over MESOR (24-h time series mean) of 65% (95% confidence interval [CI]: 49-81%). Importantly, several of these human plasma metabolites, including specific acylcarnitines and phospholipids, were hitherto not known to be 24-h variant. These findings represent an important baseline and will be useful in guiding the design and interpretation of future metabolite-based studies. (Author correspondence: or ).

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > Biochemistry and Physiology
Authors :
Date : August 2012
Identification Number : 10.3109/07420528.2012.699122
Additional Information : This is an electronic version of an article published in Chronobiology International, v.29, issue 7 (p.868-881), August 2012. Chronobiology International is available online at:
Depositing User : Symplectic Elements
Date Deposited : 02 Nov 2012 09:49
Last Modified : 23 Sep 2013 19:38

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