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Cited by 870Pharmacogenetics and Drug MetabolismDrug Transport and Resistance MechanismsDigestive system and related health

THE HUMAN INTESTINAL CYTOCHROME P450 “PIE”

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Paine, Mary F., Hart, Heather L., Ludington, Shana S., Haining, Robert L., Rettie, Allan E., Zeldin, Darryl C.·2006·Drug Metabolism and Disposition
DOI 10.1124/dmd.105.008672PMC PMC2222892
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Abstract

Cytochromes P450 (P450s) 3A, 2C, and 1A2 constitute the major "pieces" of the human liver P450 "pie" and account, on average, for 40, 25, and 18%, respectively, of total immunoquantified P450s (J Pharmacol Exp Ther 270:414-423, 1994). The P450 profile in the human small intestine has not been fully characterized. Therefore, microsomes prepared from mucosal scrapings from the duodenal/jejunal portion of 31 human donor small intestines were analyzed by Western blot using selective P450 antibodies. P450s 3A4, 2C9, 2C19, and 2J2 were detected in all individuals and ranged from 8.8 to 150, 2.9 to 27, <0.6 to 3.9, and <0.2 to 3.1 pmol/mg, respectively. CYP2D6 was detected in 29 individuals and ranged from <0.2 to 1.4 pmol/mg. CYP3A5 was detected readily in 11 individuals, with a range (average) of 4.9 to 25 (16) pmol/mg that represented from 3 to 50% of total CYP3A (CYP3A4 + CYP3A5) content. CYP1A1 was detected readily in three individuals, with a range (average) of 3.6 to 7.7 (5.6) pmol/mg. P450s 1A2, 2A6, 2B6, 2C8, and 2E1 were not or only faintly detected. As anticipated, average CYP3A content (50 pmol/mg) was the highest. Excluding CYP1A1, the remaining enzymes had the following rank order: 2C9 > 2C19 > 2J2 > 2D6 (8.4, 1.1, 0.9, and 0.5 pmol/mg, respectively). Analysis of a pooled preparation of the 31 donor specimens substantiated these results. In summary, as in the liver, large interindividual variation exists in the expression levels of individual P450s. On average, CYP3A and CYP2C9 represents the major pieces of the intestinal P450 pie, accounting for 80 and 15%, respectively, of total immunoquantified P450s.

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  • In the small intestine, CYP3A4 is the most abundant CYP enzyme (~80%), followed by CYP2C9 (~15%), CYP2C19 (2%), CYP2J2 (<2%), and CYP2D6 (<1%).

    “The CYPs in the small intestine were characterized by Paine et al. [17], and CYP3A4 was found to be the most abundant CYP enzyme (~80%), followed by CYP2C9 (~15%), CYP2C19 (2%), CYP2J2 (<2%) and CYP2D6 (<1%).”

    From Inhibition of Human Cytochrome P450 Enzymes by Bacopa monnieri Standardized Extract and Constituents (2014) · cites this paper as Paine et al. [17]

    The Discussion reports the stated rank order and percentages for proximal small-intestinal P450s. However, its ~80% figure is for CYP3A as a group, not CYP3A4 alone; the Abstract notes that CYP3A5 contributed 3–50% of total CYP3A content in individuals where it was detected. (LLM, conf=0.90)

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Cited by

Sorted by citations

Authors
Paine, M. F., Hart, H. L., Ludington, S. S., Haining, R. L., Rettie, A. E., & Zeldin, D. C.
Affiliations
  • University of North Carolina at Chapel Hill (US)
  • West Virginia University (US)
  • University of Washington (US)
  • National Institutes of Health (US)
ORCID
Venue
Drug Metabolism and Disposition
Publisher
Elsevier BV
Published
2006-05
Volume
34
Issue
5
Pages
880-886
ISSN
0090-9556 (ISSN-L)
DOI
10.1124/dmd.105.008672
PMC
PMC2222892
OpenAlex
W2111668019
Cited by
870
References
1
Citations by year
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FWCI
38.81
Type
journal article
Language
en
Open access
Licence
Locations
  • Drug Metabolism and Disposition (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (Z01-ES025034)
  • National Institute of General Medical Sciences (GM-38149, GM32165, P01GM032165, R37GM038149)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Digestive system and related health
Keywords
small intestine, CYP3A4, CYP3A5, CYP2C9, CYP2C19, CYP2J2, CYP2D6, CYP1A1, interindividual variability, duodenum, jejunum, drug metabolism, CYP2C8, CYP2E1, CYP2A6, CYP2B6, CYP1A2
MeSH terms
Adolescent, Adult, Colon, Cytochrome P-450 Enzyme System, Duodenum, Female, Humans, Intestinal Mucosa, Intestine, Small, Intestines, Isoenzymes, Male, Microsomes, Middle Aged, Recombinant Proteins, Blotting, Western

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