title: PXR-mediated induction of human CYP3A4 and mouse Cyp3a11 by the glucocorticoid budesonide.
abstract: Budesonide, a glucocorticoid with a high first-pass metabolism, is used for the oral treatment of inflammatory bowel disease. Cytochrome P450 3A4 (CYP3A4) is an enzyme involved in the metabolism of numerous drugs, including budesonide. Since inhibition or induction of CYP3A4 is often the cause of drug-drug interactions we analyzed how budesonide affects the activity and expression of this enzyme. CYP3A4 activity was assessed by the metabolism of a luminogenic substrate (luciferin-benzylether) using recombinant human CYP3A4 protein. We observed no inhibition of the metabolism in the presence of budesonide at concentrations up to 25 microM. Induction experiments in human LS180 colon carcinoma cells showed an increased expression of CYP3A4 mRNA after budesonide treatment. Transactivation assays revealed that budesonide activates the CYP3A4 promoter via the pregnane X receptor (PXR). In mice, oral budesonide administration (25mg/kg) for 4 days induced the murine homolog Cyp3a11 in the intestine 3-fold, whereas liver expression was notably less influenced. In knockout mice devoid of PXR, budesonide-mediated inductions were reduced compared to wild-type mice. In conclusion, we could demonstrate that budesonide is not an efficient inhibitor but rather an inducer of CYP3A via a PXR-mediated mechanism. In vivo, however, oral budesonide administration to mice showed only modest gene induction, which occurred mainly in the intestine. Therefore, the risk for budesonide-mediated drug interactions seems to be low but cannot be ruled out entirely.
authors.affiliation: Division of Experimental Therapy, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Zimmermann
authors.forename: Robert A B
authors.initials: RA
authors.lastname: van Waterschoot
authors.forename: Stefan
authors.initials: S
authors.lastname: Harmsen
authors.forename: Angelika
authors.initials: A
authors.lastname: Maier
authors.forename: Heike
authors.initials: H
authors.lastname: Gutmann
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Schinkel
mesh_terms: D000818:Animals; D019819:Budesonide / Q000494:pharmacology*; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D018345:Mice, Knockout; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000502:physiology*
chemical_list: D005938:Glucocorticoids; D008565:Membrane Proteins; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; D019819:Budesonide; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human