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Biomarker Discovery for Cytochrome P450 1A2 Activity Assessment in Rats, Based on Metabolomics

Cytochrome P450 1A2 (CYP1A2) is one of the major CYP450 enzymes (CYPs) in the liver, and participates in the biotransformation of various xenobiotics and endogenous signaling molecules. The expression and activity of CYP1A2 show large individual differences, due to genetic and environmental factors....

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Autores principales: Pu, Xiao, Gao, Yiqiao, Li, Ruiting, Li, Wei, Tian, Yuan, Zhang, Zunjian, Xu, Fengguo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523085/
https://www.ncbi.nlm.nih.gov/pubmed/31003543
http://dx.doi.org/10.3390/metabo9040077
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author Pu, Xiao
Gao, Yiqiao
Li, Ruiting
Li, Wei
Tian, Yuan
Zhang, Zunjian
Xu, Fengguo
author_facet Pu, Xiao
Gao, Yiqiao
Li, Ruiting
Li, Wei
Tian, Yuan
Zhang, Zunjian
Xu, Fengguo
author_sort Pu, Xiao
collection PubMed
description Cytochrome P450 1A2 (CYP1A2) is one of the major CYP450 enzymes (CYPs) in the liver, and participates in the biotransformation of various xenobiotics and endogenous signaling molecules. The expression and activity of CYP1A2 show large individual differences, due to genetic and environmental factors. In order to discover non-invasive serum biomarkers associated with hepatic CYP1A2, mass spectrometry-based, untargeted metabolomics were first conducted, in order to dissect the metabolic differences in the serum and liver between control rats and β-naphthoflavone (an inducer of CYP1A2)-treated rats. Real-time reverse transcription polymerase chain reaction and pharmacokinetic analysis of phenacetin and paracetamol were performed, in order to determine the changes of mRNA levels and activity of CYP1A2 in these two groups, respectively. Branched-chain amino acids phenylalanine and tyrosine were ultimately focalized, as they were detected in both the serum and liver with the same trends. These findings were further confirmed by absolute quantification via a liquid chromatography–tandem mass spectrometry (LC-MS/MS)-based targeted metabolomics approach. Furthermore, the ratio of phenylalanine to tyrosine concentration was also found to be highly correlated with CYP1A2 activity and gene expression. This study demonstrates that metabolomics can be a potentially useful tool for biomarker discovery associated with CYPs. Our findings contribute to explaining interindividual variations in CYP1A2-mediated drug metabolism.
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spelling pubmed-65230852019-06-03 Biomarker Discovery for Cytochrome P450 1A2 Activity Assessment in Rats, Based on Metabolomics Pu, Xiao Gao, Yiqiao Li, Ruiting Li, Wei Tian, Yuan Zhang, Zunjian Xu, Fengguo Metabolites Article Cytochrome P450 1A2 (CYP1A2) is one of the major CYP450 enzymes (CYPs) in the liver, and participates in the biotransformation of various xenobiotics and endogenous signaling molecules. The expression and activity of CYP1A2 show large individual differences, due to genetic and environmental factors. In order to discover non-invasive serum biomarkers associated with hepatic CYP1A2, mass spectrometry-based, untargeted metabolomics were first conducted, in order to dissect the metabolic differences in the serum and liver between control rats and β-naphthoflavone (an inducer of CYP1A2)-treated rats. Real-time reverse transcription polymerase chain reaction and pharmacokinetic analysis of phenacetin and paracetamol were performed, in order to determine the changes of mRNA levels and activity of CYP1A2 in these two groups, respectively. Branched-chain amino acids phenylalanine and tyrosine were ultimately focalized, as they were detected in both the serum and liver with the same trends. These findings were further confirmed by absolute quantification via a liquid chromatography–tandem mass spectrometry (LC-MS/MS)-based targeted metabolomics approach. Furthermore, the ratio of phenylalanine to tyrosine concentration was also found to be highly correlated with CYP1A2 activity and gene expression. This study demonstrates that metabolomics can be a potentially useful tool for biomarker discovery associated with CYPs. Our findings contribute to explaining interindividual variations in CYP1A2-mediated drug metabolism. MDPI 2019-04-18 /pmc/articles/PMC6523085/ /pubmed/31003543 http://dx.doi.org/10.3390/metabo9040077 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Pu, Xiao
Gao, Yiqiao
Li, Ruiting
Li, Wei
Tian, Yuan
Zhang, Zunjian
Xu, Fengguo
Biomarker Discovery for Cytochrome P450 1A2 Activity Assessment in Rats, Based on Metabolomics
title Biomarker Discovery for Cytochrome P450 1A2 Activity Assessment in Rats, Based on Metabolomics
title_full Biomarker Discovery for Cytochrome P450 1A2 Activity Assessment in Rats, Based on Metabolomics
title_fullStr Biomarker Discovery for Cytochrome P450 1A2 Activity Assessment in Rats, Based on Metabolomics
title_full_unstemmed Biomarker Discovery for Cytochrome P450 1A2 Activity Assessment in Rats, Based on Metabolomics
title_short Biomarker Discovery for Cytochrome P450 1A2 Activity Assessment in Rats, Based on Metabolomics
title_sort biomarker discovery for cytochrome p450 1a2 activity assessment in rats, based on metabolomics
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523085/
https://www.ncbi.nlm.nih.gov/pubmed/31003543
http://dx.doi.org/10.3390/metabo9040077
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