The Human Intestinal Cytochrome P450 “Pie”

Abstract

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.

MFSD2A Promotes Endothelial Generation of Inflammation-Resolving Lipid Mediators and Reduces Colitis in Mice

“…In this work, we show MFSD2A in the gut to be exclusively expressed in the endothelium and to control important biological functions of the intestinal vasculature, including its ability to mount a proper anti-inflammatory response. Moreover, we demonstrate that the generation of EpDPEs and the beneficial effects exerted by MFSD2A overexpression, are mediated both in vivo and in vitro by CYP2C, one of the major isoforms of the CYP450 family expressed in the intestine 25 , that co-localize with MFSD2A in the endoplasmic reticulum. This is consistent with the notion that ω-3 fatty acids are poor substrates of COX and LOX enzymes 38 , whereas they are highly efficient alternative substrates for numerous isoforms of CYP epoxygenases 39 .…”

“…The CYP2C subfamily represents one of the two major pieces of the intestinal P450 pie 25 . To verify whether the beneficial effects exerted by MFSD2A overexpression on HIMECs depends on its capability to promote CYP2C-derived metabolites of DHA, we first analyzed whether MFSD2A and CYP2C co-localized within the endoplasmic reticulum.…”

The effect of CYP3A5 polymorphism on dose-adjusted cyclosporine concentration in renal transplant recipients: a meta-analysis

“…5 CYP3A4 is abundantly and constitutively expressed in liver and intestine. 6 According to published literature, the expression of CYP3A4 is limitedly influenced by genetic factors. 7 Although a number of singlenucleotide polymorphisms for CYP3A4 have been identified, most of them are rare and not reported to affect its activity.…”

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

“…21,22 The prevalence of these polymorphisms varies in different populations and hence the likelihood of expressing a particular genotype/phenotype varies with ethnicity. In Caucasians, B80% will have wild-type 2C9 alleles and B20% the Intestinal CYPs: 3A (80%), 2C9 (B14%) 132 Liver CYPs: 3A4/5 (29%), 2C (18%), 1A2 (13%) 133 Highest levels of 3A in duodenum and middle jejunum, declining in the distal jejunum and ileum 134 Voriconazole and itraconazole have extensive interactions via the CYP system Relative distribution of each transporter varies in intestines, kidney, liver and brain Genetic variants have been described for almost all the transporters listed here (references describing genetic variants are in bold). As several antifungals interact with these transporters in vitro, potentially they may interact in vivo.…”