Enterocytic CYP3A4 in a paediatric population: developmental changes and the effect of coeliac disease and cystic fibrosis.

Abstract

AIMS 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.

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