Enterocytic CYP3A4 in a paediatric population: developmental changes and the effect of coeliac disease and cystic fibrosis.
OBJECTIVE
To investigate the effects of age and disease states on the expression and activity of intestinal CYP3A4 in a paediatric population.


METHODS
Duodenal biopsies and surgical sections were collected from 104 paediatric patients (age range 2 weeks to 17 years) and from 11 foetuses. An S9 fraction was prepared in each case. CYP3A4 expression was assessed by Western blotting and by immunohistochemistry; activity was measured by the rate of formation of 6beta-hydroxytestosterone from testosterone. Villin expression was used as a marker of enterocyte harvest to normalize CYP3A4 expression and activity data.


RESULTS
In the 74 histologically normal paediatric biopsies there were statistically significant increases in CYP3A4 expression (r2 = 0.19, P = 0.001) and activity (r2 = 0.17, P = 0.02) with age. CYP3A4 was practically absent in fetal duodenum and was expressed at relatively low levels in neonates (P < 0.05 between neonates and children > 5 years). Active coeliac disease resulted in significant (P < 0.001) decreases in CYP3A4 expression and activity.


CONCLUSIONS
Duodenal CYP3A4 is present at significantly lower levels in neonates and in patients with active coeliac disease. This may have clinical significance with respect to the oral bioavailability of CYP3A4 substrates.
Johnson
T N
TN
University of Sheffield, Section of Molecular Pharmacology and Pharmacogenetics, Division of Clinical Sciences, The Royal Hallamshire Hospital, Sheffield, UK. T.N.Johnson@sheffield.ac.uk
Tanner
M S
MS
Taylor
C J
CJ
Tucker
G T
GT
D000293:Adolescent; D000367:Age Factors; D002446:Celiac Disease / Q000201:enzymology* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000201:enzymology* / Q000473:pathology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006801:Humans; D007118:Immunoassay; D007223:Infant; D007231:Infant, Newborn; D007422:Intestines / Q000201:enzymology*; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism*
D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human