Selective induction of intestinal CYP3A23 by 1alpha,25-dihydroxyvitamin D3 in rats.
Enhancement of CYP3A transcription in both the small intestine and liver of the mouse by activation of a VDR signaling pathway was shown recently by Makishima et al. (Science, 2002). However, in humans and rats, hepatic VDR content is much lower than that found in small intestine, suggesting the possibility of tissue-selective responses to 1,25(OH)(2)D(3). The purpose of this study was to determine the effect of 1,25(OH)(2)D(3) on intestinal and hepatic CYP3A expression in the rat. We found that an acute intraperitoneal treatment (every 48 h) in adult male rats with 1,25(OH)(2)D(3) induced CYP3A transcription selectively in small intestine, but not in liver. At a dose of 100 ng, there was a 6.6-fold increase in intestinal CYP3A23 mRNA after the third treatment (p < 0.05). There were concordant effects of 1,25(OH)(2)D(3) treatment on intestinal CYP3A23 protein levels; 2.2-fold (p < 0.05), 3.5-fold (p < 0.05) and 4.8-fold (p < 0.01) increase following 1-3 doses of 100 ng 1,25(OH)(2)D(3), respectively. In contrast, there was no significant change of CYP3A23 protein content in liver at the 1,25(OH)(2)D(3) doses tested. In support of these findings, there was a 366-fold and 77-fold higher level of VDR mRNA expression in the respective rat and human jejunal mucosa, compared to the liver. These data suggest that the human liver will be less sensitive than the intestine to the transcriptional effects of 1,25(OH)(2)D(3) and that this regulatory pathway may contribute to inter-individual variability in constitutive intestinal CYP3A4 expression.
Xu
Yang
Y
Department of Pharmaceutics, University of Washington, Seattle, 98195-7610, USA.
Iwanaga
Kazunori
K
Zhou
Changcheng
C
Cheesman
Matthew J
MJ
Farin
Federico
F
Thummel
Kenneth E
KE
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002117:Calcitriol / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000201:enzymology; D007583:Jejunum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism
D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C415842:Cyp3a9 protein, rat; D051544:Cytochrome P-450 CYP3A; C022657:steroid hormone 6-beta-hydroxylase; D010089:Oxidoreductases, N-Demethylating; D002117:Calcitriol