Dietary phytochemicals regulate whole-body CYP1A1 expression through an arylhydrocarbon receptor nuclear translocator–dependent system in gut
Shinji Ito, … , SunHee Yim, Frank J. Gonzalez
Shinji Ito, … , SunHee Yim, Frank J. Gonzalez
Published July 2, 2007
Citation Information: J Clin Invest. 2007;117(7):1940-1950. https://doi.org/10.1172/JCI31647.
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Research Article Metabolism

Dietary phytochemicals regulate whole-body CYP1A1 expression through an arylhydrocarbon receptor nuclear translocator–dependent system in gut

Abstract

Cytochrome P450 1A1 (CYP1A1) is one of the most important detoxification enzymes due to its broad substrate specificity and wide distribution throughout the body. On the other hand, CYP1A1 can also produce highly carcinogenic intermediate metabolites through oxidation of polycyclic aromatic hydrocarbons. We describe what we believe to be a novel regulatory system for whole-body CYP1A1 expression by a factor originating in the gut. A mutant mouse was generated in which the arylhydrocarbon receptor nuclear translocator (Arnt) gene is disrupted predominantly in the gut epithelium. Surprisingly, CYP1A1 mRNA expression and enzymatic activities were markedly elevated in almost all non-gut tissues in this mouse line. The induction was even observed in early-stage embryos in pregnant mutant females. Interestingly, the upregulation was CYP1A1 selective and lost upon administration of a synthetic purified diet. Moreover, the increase was recovered by addition of the natural phytochemical indole-3-carbinol to the purified diet. These results suggest that an Arnt-dependent pathway in gut has an important role in regulation of the metabolism of dietary CYP1A1 inducers and whole-body CYP1A1 expression. This machinery might be involved in naturally occurring carcinogenic processes and/or other numerous biological responses mediated by CYP1A1 activity.

Authors

Shinji Ito, Chi Chen, Junko Satoh, SunHee Yim, Frank J. Gonzalez

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Figure 2

Intestinal epithelium–specific disruption of Hif1a gene.

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Intestinal epithelium–specific disruption of Hif1a gene. ...
(A) Schematic structure of the modified Hif1a allele. The probe used in the Southern blot analysis is indicated. (B) Southern blot analysis for the Hif1a allele. Filled and open triangles indicate Hif1a flΔneo and exon 13–15–deleted allele, respectively (18). Fragments corresponding to the Hif1a flΔneo allele were only detected in Hif-1αΔIE mice. w, whole tissue; e, epithelial cells. (C) Primers used for the detection of intact Hif1a transcripts. (D) Relative expression levels of the intact Hif1a transcripts measured by qPCR. White and black bars represent the Hif-1αF/F and Hif-1αΔIE mice, respectively. Average values for 4 mice (for intestine) or individual values in 2 mice (for lung and heart) in each group are shown. Relative values were calculated from the average expression level in the small intestine of the Hif-1αF/F mice defined as standard (set as 1.0). Error bars indicate SEM. Statistical significance between the average of Hif-1αF/F and Hif-1αΔIE mice in the same tissue was examined. *P < 0.05; ***P < 0.001.