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Ontogeny of cytochrome 3A and P‐glycoprotein in the human intestine
Author(s) -
Fakhoury M.,
Litalien C.,
Medard Y.,
Peuchmaur M.,
JacqzAigrain E.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.189
Subject(s) - cyp3a , villin , cyp3a4 , biology , messenger rna , p glycoprotein , cyp3a5 , polyclonal antibodies , medicine , ileum , microbiology and biotechnology , small intestine , enterocyte , endocrinology , gene expression , andrology , cytochrome p450 , antibody , immunology , gene , metabolism , genotype , biochemistry , actin , multiple drug resistance , antibiotics
Cytochromes P4503A (the predominant CYP450 subfamily) and P‐glycoprotein (P‐gp, an efflux plasma membrane protein) are mainly located in enterocytes and hepatocytes and reduce the absorption of many drugs. During the neonatal period, a shift between CYP3A7, the fetal form, and CYP3A4 occurs in the liver but data on expression of the CYP3A/P‐gp complex in the intestine are very limited. Localisation and expression of CYP3A and P‐gp were studied in 59 normal duodenal biopsies from Caucasian children aged 1 month to 18 years. The immunoblot analysis (polyclonal antibody Nuage) showed that CYP3A was expressed in half the enterocytes until 6 months and in all the older children. P‐gp (monoclonal antibody “C494”) was expressed at the apical surface of all enterocytes. mRNA quantification of the 3 CYP3A isoforms (3A4, 3A5, 3A7) and P‐gp was performed using highly specific real time RT‐PCR (normalisation with villin). CYP3A4 and CYP3A5 mRNA expression were high at birth and decreased afterwards (0.04 ‐ 0.25 and 0.001 to 0.46 respectively, including expression of mutated allele CYP3A5*3), CYP3A7 mRNA was detected in 35% of the samples at a low level. P‐gp mRNA was found variably expressed from 0.08 to 1 with a significant increase between 6 and 12 months of age. Our results showed that neonates and infants have a significant intestinal expression of CYP3A and P‐gp mRNA. Additional studies are required to quantify protein activity and determine the clinical impact of these results. Clinical Pharmacology & Therapeutics (2004) 75 , P50–P50; doi: 10.1016/j.clpt.2003.11.189