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

Jie Cheng, Chi Chen, Krausz W. Kristopher, Soumen K. Manna, Mike Scerba, Fred K. Friedman, Hans Luecke, Jeffrey R. Idle, Frank J. Gonzalez

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)37-47
Number of pages11
JournalToxicological Sciences
Volume135
Issue number1
DOIs
StatePublished - Sep 2013

Keywords

  • 2-piperidone
  • Biomarker
  • CYP2E1
  • Cadaverine
  • Metabolomics

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