Selective induction of intestinal CYP3A23 by 1α,25-dihydroxyvitamin D3 in rats


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Abstract

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)2D3. The purpose of this study was to determine the effect of 1,25(OH)2D3 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)2D3 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)2D3 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)2D3, respectively. In contrast, there was no significant change of CYP3A23 protein content in liver at the 1,25(OH)2D3 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)2D3 and that this regulatory pathway may contribute to inter-individual variability in constitutive intestinal CYP3A4 expression.

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