1. Academic Validation
  2. Identification of 2-piperidone as a biomarker of CYP2E1 activity through metabolomic phenotyping

Identification of 2-piperidone as a biomarker of CYP2E1 activity through metabolomic phenotyping

  • Toxicol Sci. 2013 Sep;135(1):37-47. doi: 10.1093/toxsci/kft143.
Jie Cheng 1 Chi Chen Krausz W Kristopher Soumen K Manna Mike Scerba Fred K Friedman Hans Luecke Jeffrey R Idle Frank J Gonzalez
Affiliations

Affiliation

  • 1 Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Abstract

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.

Keywords

2-piperidone; CYP2E1; biomarker; cadaverine.; metabolomics.

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