Identification of 2-Piperidone as a Biomarker of CYP2E1 Activity Through Metabolomic Phenotyping

Cheng, Jie; Chen, Chi; Kristopher, Krausz W.; Manna, Soumen K.; Scerba, Mike; Friedman, Fred K.; Luecke, Hans; Idle, Jeffrey R.; Gonzalez, Frank J. (2013). Identification of 2-Piperidone as a Biomarker of CYP2E1 Activity Through Metabolomic Phenotyping. Toxicological sciences, 135(1), pp. 37-47. Oxford University Press 10.1093/toxsci/kft143

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Cytochrome P450 2E1 (CYP2E1) is a key enzyme in the metabolic activation of many low molecular weight toxicants and also an important contributor to oxidative stress. A noninvasive method to monitor CYP2E1 activity in vivo would be of great value for studying the role of CYP2E1 in chemical-induced toxicities and stress-related diseases. In this study, a mass spectrometry-based metabolomic approach was used to identify a metabolite biomarker of CYP2E1 through comparing the urine metabolomes of wild-type (WT), Cyp2e1-null, and CYP2E1-humanized mice. Metabolomic analysis with multivariate models of urine metabolites revealed a clear separation of Cyp2e1-null mice from WT and CYP2E1-humanized mice in the multivariate models of urine metabolomes. Subsequently, 2-piperidone was identified as a urinary metabolite that inversely correlated to the CYP2E1 activity in the three mouse lines. Backcrossing of WT and Cyp2e1-null mice, together with targeted analysis of 2-piperidone in mouse serum, confirmed the genotype dependency of 2-piperidone. The accumulation of 2-piperidone in the Cyp2e1-null mice was mainly caused by the changes in the biosynthesis and degradation of 2-piperidone because compared with the WT mice, the conversion of cadaverine to 2-piperidone was higher, whereas the metabolism of 2-piperidone to 6-hydroxy-2-piperidone was lower in the Cyp2e1-null mice. Overall, untargeted metabolomic analysis identified a correlation between 2-piperidone concentrations in urine and the expression and activity of CYP2E1, thus providing a noninvasive metabolite biomarker that can be potentially used in to monitor CYP2E1 activity.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Hepatology

UniBE Contributor:

Idle, Jeffrey

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1096-6080

Publisher:

Oxford University Press

Language:

English

Submitter:

Lilian Karin Smith-Wirth

Date Deposited:

18 Jun 2014 09:10

Last Modified:

23 Oct 2019 17:20

Publisher DOI:

10.1093/toxsci/kft143

Uncontrolled Keywords:

CYP2E1, biomarker, metabolomics, 2-piperidone, cadaverine

BORIS DOI:

10.7892/boris.53760

URI:

https://boris.unibe.ch/id/eprint/53760

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