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CYP2C19 plays a major role in the hepatic N-oxidation of cotinine

Yadira X Perez-Paramo, Christy J.W. Watson, Gang Chen and Philip Lazarus
Drug Metabolism and Disposition February 23, 2022, DMD-AR-2021-000624; DOI: https://doi.org/10.1124/dmd.121.000624
Yadira X Perez-Paramo
1OMNI-Biomarker Development, Genentech Inc., United States
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Christy J.W. Watson
2Pharmaceutical Sciences, Washington State University, United States
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Gang Chen
3Pharmaceutical Sciences, WSU College of Pharmacy, United States
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Philip Lazarus
4Pharmaceutical Sciences, Washington State University College of Pharmacy, United States
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  • For correspondence: phil.lazarus@wsu.edu
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Abstract

The major mode of metabolism of nicotine is via the formation of cotinine by the enzyme cytochrome P450 (CYP) 2A6. Cotinine undergoes further CYP2A6-mediated metabolism by hydroxylation to 3-hydroxycotinine and norcotinine but can also form cotinine-N-glucuronide and cotinine-N-oxide (COX). The goal of the present study was to investigate the enzymes that catalyze COX formation and determine whether genetic variation in these enzymes may affect this pathway. Specific inhibitors of major hepatic cytochrome P450 (CYP) enzymes were used in cotinine-N-oxidation reactions using pooled human liver microsomes (HLM). COX formation was monitored by ultra-high pressure liquid chromatography-mass spectrometry and enzyme kinetic analysis was performed using microsomes from CYP-overexpressing HEK293 cell lines. Genotype-phenotype analysis was performed in a panel of 113 human liver specimens. Inhibition of COX formation was only observed in HLM when using inhibitors of CYPs 2A6, 2B6, 2C19, 2E1, and 3A4. Microsomes from cells overexpressing CYPs 2A6 or 2C19 exhibited similar N-oxidation activity against cotinine, with Vmax/KM values of 4.4 and 4.2 nL/min/mg, respectively. CYP2B6-, CYP2E1-, and CYP3A4-overexpressing microsomes were also active in COX formation. Significant associations (p<0.05) were observed between COX formation and genetic variants in CYPs 2C19 (*2 and *17 alleles) in HLM. These results demonstrate that genetic variants in CYP2C19 are associated with decreased COX formation, potentially affecting the relative levels of cotinine in the plasma or urine of smokers and ultimately affecting recommended smoking cessation therapies.

Significance Statement This study is the first to elucidate the enzymes responsible for cotinine-N-oxide formation and genetic variants that affect this biological pathway. Genetic variants in CYP2C19 have the potential to modify NMR in smokers and could affect pharmacotherapeutic decisions for smoking cessation treatments.

  • CYP2C19
  • drug metabolism
  • genetic polymorphism
  • genotype
  • liver microsomes
  • liver/hepatic
  • nicotine
  • pharmacogenetics
  • © 2020 The Authors. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial purposes.
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Drug Metabolism and Disposition: 51 (2)
Drug Metabolism and Disposition
Vol. 51, Issue 2
1 Feb 2023
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CYP2C19 variants and cotinine-N-oxide metabolism

Yadira X Perez-Paramo, Christy J.W. Watson, Gang Chen and Philip Lazarus
Drug Metabolism and Disposition February 23, 2022, DMD-AR-2021-000624; DOI: https://doi.org/10.1124/dmd.121.000624

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OtherArticle

CYP2C19 variants and cotinine-N-oxide metabolism

Yadira X Perez-Paramo, Christy J.W. Watson, Gang Chen and Philip Lazarus
Drug Metabolism and Disposition February 23, 2022, DMD-AR-2021-000624; DOI: https://doi.org/10.1124/dmd.121.000624
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