Received for publication May 23, 2005.
Revised July 26, 2005.
Accepted for publication July 26, 2005.

Localization and mRNA expression of CY3A and P-gp in human duodenum as a function of age

Abstract

Cytochromes P450 3A (CYP3A) and P-glycoprotein (P-gp) are mainly located in enterocytes and hepatocytes. The CYP3A/P-gp system contributes to the first pass metabolism of many drugs, resulting in a limited bioavailability. During the neonatal period, a shift between CYP3A7, the fetal form, and CYP3A4 occurs in the liver but data on the expression of the CYP3A/P-gp complex in the intestine are very limited. 59 normal duodenal biopsies from Caucasian children aged 1 month to 17 years were studied. Localization of the proteins by immunohistochemistry analysis was performed using a polyclonal antibody "Nuage" anti-CYP3A and a monoclonal antibody "C494" anti-P-gp. The mRNA quantification was performed using highly specific real time RT-PCR. Villin mRNA quantification was used for normalization. CYP3A protein was detected in all enterocytes in the samples from patients over 6 months of age while it was not in younger samples. P-gp protein was expressed at the apical and upper lateral surfaces of the enterocytes. CYP3A isoforms and P-gp mRNA levels were highly variable. CYP3A4 and CYP3A5 mRNA levels were high during the first year of life and decreased with age while CYP3A7 was detected at a low level in 64% of samples, whatever the age. P-gp mRNA expression level was also highly variable. Our results showed that neonates and infants had a significant expression of CYP3A and P-gp mRNA in the intestine, suggesting a different maturation profile of CYP3A and P-gp with age in the liver and the intestine.

Key words: CYP3A, gastrointestinal pharmacology, human CYP enzymes, p-glycoprotein