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 human intestinal villi and may account for significant "first-pass" prehepatic metabolism of a number of drugs in the intestine. Celiac disease results in small intestinal atrophy. We hypothesized that this would result in a loss of CYP3A.


METHODS
Formalin-fixed jejunal biopsy specimens taken from nine patients with celiac disease at variable times before and after treatment with a gluten-free diet were immunoperoxidase stained after incubation with anti-CYP3A4 rabbit antisera (1:2000 dilution). The amount of immunoreactive CYP3A was determined by two observers who were blinded to the treatment states of the patients. Staining intensity was graded on a numerical scale from 1 to 4+ on the basis of intensity of staining in individual enterocytes, as well as the total number of enterocytes stained.


RESULTS
Slides of biopsy specimens 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 specimens (p < 0.05, Wilcoxon signed-rank test).


CONCLUSIONS
We conclude that patients with celiac disease have low intestinal CYP3A immunoreactivity and that treatment with a gluten-free diet is associated with an increase in intestinal CYP3A immunoreactive protein. Our findings suggest that intestinal disease and variability in intestinal CYP3A activity might be an unexamined variable that may contribute to interindividual variability in drug disposition.
Department of Histopathology, Vanderbilt University, Nashville, TN 37232-6602, USA.
C C
CC
Lang
R M
RM
Brown
M T
MT
Kinirons
M A
MA
Deathridge
F P
FP
Guengerich
D
D
Kelleher
D S
DS
O'Briain
F K
FK
Ghishan
A J
AJ
Wood
D000328:Adult; D001706:Biopsy; D002446:Celiac Disease / Q000178:diet therapy* / Q000201:enzymology*; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D005983:Glutens / Q000008:administration & dosage; D006801:Humans; D007124:Immunoenzyme Techniques; D007421:Intestine, Small / Q000201:enzymology*; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D015203:Reproducibility of Results
D005983:Glutens; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1