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Selective induction of intestinal CYP3A23 by 1alpha,25-dihydroxyvitamin D3 in rats.
Biochem Pharmacol 2006; 72(3):385-92BP

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)(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.

Authors+Show Affiliations

Department of Pharmaceutics, University of Washington, Seattle, 98195-7610, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16769037

Citation

Xu, Yang, et al. "Selective Induction of Intestinal CYP3A23 By 1alpha,25-dihydroxyvitamin D3 in Rats." Biochemical Pharmacology, vol. 72, no. 3, 2006, pp. 385-92.
Xu Y, Iwanaga K, Zhou C, et al. Selective induction of intestinal CYP3A23 by 1alpha,25-dihydroxyvitamin D3 in rats. Biochem Pharmacol. 2006;72(3):385-92.
Xu, Y., Iwanaga, K., Zhou, C., Cheesman, M. J., Farin, F., & Thummel, K. E. (2006). Selective induction of intestinal CYP3A23 by 1alpha,25-dihydroxyvitamin D3 in rats. Biochemical Pharmacology, 72(3), pp. 385-92.
Xu Y, et al. Selective Induction of Intestinal CYP3A23 By 1alpha,25-dihydroxyvitamin D3 in Rats. Biochem Pharmacol. 2006 Jul 28;72(3):385-92. PubMed PMID: 16769037.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Selective induction of intestinal CYP3A23 by 1alpha,25-dihydroxyvitamin D3 in rats. AU - Xu,Yang, AU - Iwanaga,Kazunori, AU - Zhou,Changcheng, AU - Cheesman,Matthew J, AU - Farin,Federico, AU - Thummel,Kenneth E, PY - 2005/12/30/received PY - 2006/04/24/revised PY - 2006/04/27/accepted PY - 2006/6/14/pubmed PY - 2006/8/31/medline PY - 2006/6/14/entrez SP - 385 EP - 92 JF - Biochemical pharmacology JO - Biochem. Pharmacol. VL - 72 IS - 3 N2 - 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. SN - 0006-2952 UR - https://www.unboundmedicine.com/medline/citation/16769037/Selective_induction_of_intestinal_CYP3A23_by_1alpha25_dihydroxyvitamin_D3_in_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(06)00257-7 DB - PRIME DP - Unbound Medicine ER -