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Research ArticleArticle

The Revised Human Liver Cytochrome P450 “Pie”: Absolute Protein Quantification of CYP4F and CYP3A Enzymes Using Targeted Quantitative Proteomics

Scott Michaels and Michael Zhuo Wang
Drug Metabolism and Disposition August 2014, 42 (8) 1241-1251; DOI: https://doi.org/10.1124/dmd.114.058040
Scott Michaels
Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas (M.Z.W., S.M.); Wolfe Laboratories, Inc., Watertown, Massachusetts (S.M.)
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Michael Zhuo Wang
Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas (M.Z.W., S.M.); Wolfe Laboratories, Inc., Watertown, Massachusetts (S.M.)
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Abstract

The CYP4F subfamily of enzymes has been identified recently to be involved in the metabolism of endogenous compounds (arachidonic acid and leukotriene B4), nutrients (vitamins K1 and E), and xenobiotics (pafuramidine and fingolimod). CYP4F2 and CYP4F3B are reported to be expressed in the human liver. However, absolute concentrations of these enzymes in human liver microsomes (HLMs) and their interindividual variability have yet to be determined because of the lack of specific antibodies. Here, an liquid chromatography with tandem mass spectrometry (LC-MS/MS)-based targeted quantitative proteomic approach was employed to determine the absolute protein concentrations of CYP4F2 and CYP4F3B compared with CYP3A in two panels of HLMs (n = 31). As a result, the human hepatic cytochrome P450 (P450) “pie” has been revised to include the contribution of CYP4F enzymes, which amounts to 15% of the total hepatic cytochrome P450 enzymes. CYP4F3B displayed low interindividual variability (3.3-fold) in the HLM panels whereas CYP4F2 displayed large variability (21-fold). However, CYP4F2 variability decreased to 3.4-fold if the two donors with the lowest expression were excluded. In contrast, CYP3A exhibited 29-fold interindividual variability in the same HLM panels. The proposed marker reaction for CYP4F enzymes pafuramidine/DB289 M1 formation did not correlate with CYP4F protein content, suggesting alternate metabolic pathways for DB289 M1 formation in HLMs. In conclusion, CYP4F enzymes are highly expressed in the human liver and their physiologic and pharmacologic roles warrant further investigation.

Footnotes

    • Received March 11, 2014.
    • Accepted May 9, 2014.
  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant R01 GM089994].

  • dx.doi.org/10.1124/dmd.114.058040.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (8)
Drug Metabolism and Disposition
Vol. 42, Issue 8
1 Aug 2014
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Research ArticleArticle

CYP4F and Revised Human Liver P450 “Pie”

Scott Michaels and Michael Zhuo Wang
Drug Metabolism and Disposition August 1, 2014, 42 (8) 1241-1251; DOI: https://doi.org/10.1124/dmd.114.058040

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Research ArticleArticle

CYP4F and Revised Human Liver P450 “Pie”

Scott Michaels and Michael Zhuo Wang
Drug Metabolism and Disposition August 1, 2014, 42 (8) 1241-1251; DOI: https://doi.org/10.1124/dmd.114.058040
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