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The human intestinal cytochrome P450 "pie".
Mary F Paine1, Heather L Hart, Shana S Ludington
1General Clinical Research Center, Room 3005 Bldg APCF, CB# 7600, UNC Hospitals, Chapel Hill, NC 27599-7600, USA. mpaine@med.unc.edu
Drug Metabolism and Disposition: the Biological Fate of Chemicals
|February 10, 2006
Summary
This study characterizes the cytochrome P450 (CYP) enzyme profile in the human small intestine. Cytochrome P450 3A (CYP3A) and CYP2C9 are the most abundant intestinal CYPs, with significant interindividual variability.
Area of Science:
- Pharmacology
- Biochemistry
- Drug Metabolism
Background:
- Cytochromes P450 (P450s) are crucial for drug metabolism, with CYP3A, CYP2C, and CYP1A2 dominating the human liver P450 landscape.
- The P450 enzyme profile in the human small intestine remains incompletely understood, hindering comprehensive drug disposition analysis.
Purpose of the Study:
- To comprehensively characterize the expression and abundance of various Cytochrome P450 enzymes in the human small intestine.
- To compare the intestinal P450 profile with that of the liver and assess interindividual variability.
Main Methods:
- Microsomes were prepared from duodenal/jejunal mucosal scrapings of 31 human donors.
- Western blot analysis using selective P450 antibodies was employed to quantify enzyme levels.
- Immunoblotting was performed on individual samples and a pooled preparation.
Main Results:
- CYP3A4, CYP2C9, CYP2C19, and CYP2J2 were detected in all individuals, with CYP3A4 and CYP2C9 being the most abundant.
- CYP2D6 was present in most individuals, while CYP3A5 was detected in a subset.
- CYP1A1 was detected in a few individuals; CYP1A2, CYP2A6, CYP2B6, CYP2C8, and CYP2E1 were minimally detected.
- Average CYP3A and CYP2C9 constituted approximately 80% and 15% of total immunoquantified intestinal P450s, respectively.
- Significant interindividual variation in P450 expression levels was observed, similar to the liver.
Conclusions:
- The human small intestine possesses a distinct P450 profile, with CYP3A and CYP2C9 as the predominant enzymes.
- Significant interindividual variability in intestinal P450 expression highlights the importance of considering patient-specific factors in drug therapy.
- This detailed characterization provides a foundation for understanding drug absorption and metabolism in the small intestine.