Document Detail


Stable isotope- and mass spectrometry-based metabolomics as tools in drug metabolism: a study expanding tempol pharmacology.
MedLine Citation:
PMID:  23301521     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The application of mass spectrometry-based metabolomics in the field of drug metabolism has yielded important insights not only into the metabolic routes of drugs but has provided unbiased, global perspectives of the endogenous metabolome that can be useful for identifying biomarkers associated with mechanism of action, efficacy, and toxicity. In this report, a stable isotope- and mass spectrometry-based metabolomics approach that captures both drug metabolism and changes in the endogenous metabolome in a single experiment is described. Here the antioxidant drug tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) was chosen because its mechanism of action is not completely understood and its metabolic fate has not been studied extensively. Furthermore, its small size (MW = 172.2) and chemical composition (C(9)H(18)NO(2)) make it challenging to distinguish from endogenous metabolites. In this study, mice were dosed with tempol or deuterated tempol (C(9)D(17)HNO(2)) and their urine was profiled using ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Principal component analysis of the urinary metabolomics data generated a Y-shaped scatter plot containing drug metabolites (protonated and deuterated) that were clearly distinct from the endogenous metabolites. Ten tempol drug metabolites, including eight novel metabolites, were identified. Phase II metabolism was the major metabolic pathway of tempol in vivo, including glucuronidation and glucosidation. Urinary endogenous metabolites significantly elevated by tempol treatment included 2,8-dihydroxyquinoline (8.0-fold, P < 0.05) and 2,8-dihydroxyquinoline-β-d-glucuronide (6.8-fold, P < 0.05). Urinary endogenous metabolites significantly attenuated by tempol treatment including pantothenic acid (1.3-fold, P < 0.05) and isobutrylcarnitine (5.3-fold, P < 0.01). This study underscores the power of a stable isotope- and mass spectrometry-based metabolomics in expanding the view of drug pharmacology.
Authors:
Fei Li; Xiaoyan Pang; Kristopher W Krausz; Changtao Jiang; Chi Chen; John A Cook; Murali C Krishna; James B Mitchell; Frank J Gonzalez; Andrew D Patterson
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Validation Studies     Date:  2013-01-31
Journal Detail:
Title:  Journal of proteome research     Volume:  12     ISSN:  1535-3907     ISO Abbreviation:  J. Proteome Res.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-01     Completed Date:  2013-08-29     Revised Date:  2014-03-07    
Medline Journal Info:
Nlm Unique ID:  101128775     Medline TA:  J Proteome Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1369-76     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cyclic N-Oxides / pharmacokinetics,  pharmacology*,  urine
Isotopes*
Male
Metabolomics*
Mice
Mice, Inbred C57BL
Principal Component Analysis
Spin Labels
Grant Support
ID/Acronym/Agency:
ES022186/ES/NIEHS NIH HHS; R01 ES022186/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Cyclic N-Oxides; 0/Isotopes; 0/Spin Labels; 2226-96-2/tempol
Comments/Corrections

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