DECREASED INTESTINAL CYP3A IN CELIAC-DISEASE - REVERSAL AFTER SUCCESSFUL GLUTEN-FREE DIET - A POTENTIAL SOURCE OF INTERINDIVIDUAL VARIABILITY IN FIRST-PASS DRUG-METABOLISM

Background: Cytochrome P450 (CYP) 3A is constitutively expressed in hu man intestinal villi and may account for significant ''first-pass'' pr ehepatic metabolism of a number of drugs in the intestine. Celiac dise ase results in small intestinal atrophy. We hypothesized that this wou ld result in a loss of CYP3A. Methods: Formalin-fixed jejunal biopsy s pecimens taken from nine patients with celiac disease at variable time s before and after treatment with a gluten-free diet were immunoperoxi dase stained after incubation with anti-CYP3A4 rabbit antisera (1:2000 dilution). The amount of immunoreactive CYP3A was determined by two o bservers who were blinded to the treatment states of the patients. Sta ining intensity was graded on a numerical scale from 1 to 4+ on the ba sis of intensity of staining in individual enterocytes, as well as the total number of enterocytes stained. Results: Slides of biopsy specim ens from all nine untreated patients with celiac disease were graded 1 . Treatment with a gluten-free diet was associated with a significant increase in CYP3A immunoreactive protein in small bowel biopsy specime ns (p < 0.05, Wilcoxon signed-rank test). Conclusions: We conclude tha t patients with celiac disease have low intestinal CYP3A immunoreactiv ity and that treatment with a gluten-free diet is associated with an i ncrease in intestinal CYP3A immunoreactive protein. Our findings sugge st that intestinal disease and variability in intestinal CYP3A activit y might be an unexamined variable that may contribute to interindividu al variability in drug disposition.