Impact of inflammation on the duodenal mRNA expression of CYP3A and P-glycoprotein in children with Crohn's disease.
OBJECTIVE
Crohn's disease (CD) is a chronic and invalidating inflammatory bowel disease of unknown etiology. The coordinated action of the cytochrome metabolizing subfamily CYP3A and the transport protein P-glycoprotein (P-gp) in the enterocyte results in a reduced bioavailability of drugs administered orally. Cytokines modulate the expression and functionality of CYP3A and P-gp. Although P-gp results are in disagreement between animal and Caco-2 cell studies, all authors report a decrease in CYP3A levels after exposure to proinflammatory agents. In humans, CYP3A and P-gp mRNA, protein, and functionality levels were higher in various tissues in patients with CD as compared with control groups. Our study's aim was to analyze the impact of systemic inflammation on the expression of CYP3A and P-gp in duodenal normal tissue.


METHODS
We compared CYP3A and P-gp mRNA expression in 19 noninflamed duodenal biopsies from children with CD with 19 normal biopsies. We used a real-time reverse-transcription-polymerase chain reaction technique.


RESULTS
There was a high variability in the expression of the 3 CYP3A isoforms and P-gp. CYP3A4, CYP3A5, and P-gp levels were significantly higher in the CD group than in the control group.


CONCLUSIONS
CYP3A and P-gp are involved in the metabolism and transport of many drugs prescribed in CD including corticosteroids. Changes occurring in their duodenal and hepatic expression may explain important interindividual differences in the bioavailability and response to treatment. Further explorations considering protein and activity must be undertaken to understand how such changes affect drug absorption and bioavailability.
Fakhoury
May
M
Department of Paediatric Pharmacology and Pharmacogenetics, Robert Debré Hospital, Paris, France.
Lecordier
Julien
J
Medard
Yves
Y
Peuchmaur
Michel
M
Jacqz-Agrain
Evelyne
E
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000293:Adolescent; D002648:Child; D003424:Crohn Disease / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D004386:Duodenum / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012333:RNA, Messenger; D051544:Cytochrome P-450 CYP3A