Dietary phytochemicals regulate whole-body CYP1A1 expression through an arylhydrocarbon receptor nuclear translocator–dependent system in gut
Shinji Ito, Chi Chen, Junko Satoh, SunHee Yim, Frank J. Gonzalez
Shinji Ito, Chi Chen, Junko Satoh, SunHee Yim, Frank J. Gonzalez
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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 3

Gene expression profiles of ArntF/F and ArntΔIE mice under normal dietary conditions.

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Gene expression profiles of ArntF/F and ArntΔIE mice under normal dietar...
(A) Expression levels of genes expressed in a genotype-dependent manner in the intestinal tract. Each bar corresponds to an individual animal. F/F, ArntF/F (open); ΔIE, ArntΔIE (shaded). (B) CYP1A1 mRNA expression levels in the various tissues. (C) PhIP hydroxylase activities in lung microsomes isolated from ArntF/F and ArntΔIE mice. Average values for each group (n = 6) are shown. White and black bars represent the expression levels in ArntF/F and ArntΔIE mice, respectively. (D) CYP1A1 mRNA expression levels in E7.5 embryos. Dams’ genotypes are indicated. Each bar corresponds to an individual animal. A representative of 2 independent experiments is shown. mRNA expression levels were determined by qPCR. Relative values for each gene were calculated from the average expression level in the small intestine of the ArntF/F mice with FVB/N background defined as general standard (set as 1.0). Error bars indicate SEM. Statistical significance between the average values for ArntF/F and ArntΔIE mice in the same tissue was examined. ***P < 0.001.