Localization and mRNA expression of CYP3A and P-glycoprotein in human duodenum as a function of age.
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. A total of 59 normal duodenal biopsies from white 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 reverse transcription-polymerase chain reaction. Villin mRNA quantification was used for normalization. CYP3A protein was detected in all enterocytes in the samples from patients over 6 months of age, whereas 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, whereas 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.
Fakhoury
May
M
Department of Paediatric Pharmacology and Pharmacogenetics, Robert Debré Hospital, 48 Boulevard Serurier, 75019, Paris, France.
Litalien
Catherine
C
Medard
Yves
Y
Cavé
Hélène
H
Ezzahir
Nadia
N
Peuchmaur
Michel
M
Jacqz-Aigrain
Evelyne
E
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000293:Adolescent; D000367:Age Factors; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004386:Duodenum / Q000378:metabolism*; D020895:Enterocytes / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007527:Isoenzymes / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007527:Isoenzymes; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; C103123:CYP3A7 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human