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Received for publication November 30, 2005.
Revised January 31, 2006.
Accepted for publication February 1, 2006.
Cytochromes P450 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 (Shimada et al., J Pharmacol Exp Ther 270:414-23, 1994). The P450 profile in the human small intestine has not been fully characterized. Accordingly, 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. CYPs 3A4, 2C9, 2C19, and 2J2 were detected in all individuals and ranged from 8.8-150, 2.9-27, <0.6-3.9, and <0.2-3.1 pmol/mg, respectively. CYP2D6 was detected in 29 individuals and ranged from <0.2-1.4 pmol/mg. CYP3A5 was detected readily in 11 individuals, with a range (average) of 4.9-25 (16) pmol/mg that represented from 3-50% of total CYP3A (CYP3A4+CYP3A5) content. CYP1A1 was detected readily in 3 individuals, with a range (average) of 3.6-7.7 (5.6) pmol/mg. CYPs 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 represent the major pieces of the intestinal P450 pie, accounting for 80% and 15%, respectively, of total immunoquantified P450s.
Key words:
CYP expression, CYP2C, CYP2D, CYP3A, cytochrome P450 isoforms, extrahepatic cytochrome P450, extrahepatic drug metabolism, first-pass metabolism, gastrointestinal cytochrome P450, microsomes
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