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PMID: 17607366 Published · ppublish English Journal Article Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

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

The Journal of clinical investigation ·Vol. 117 ·No. 7 ·2007-07-00 ·Pages 1940-50

Ito S, Chen C, Satoh J, Yim S, Gonzalez FJ

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.

MeSH Terms
Active Transport, Cell Nucleus Animals Aryl Hydrocarbon Receptor Nuclear Translocator/genetics,metabolism Cytochrome P-450 CYP1A1/genetics,metabolism Diet Epithelium/metabolism Feces Gastric Mucosa/metabolism Gene Expression Profiling Gene Expression Regulation, Enzymologic/drug effects Hypoxia-Inducible Factor 1, alpha Subunit/genetics,metabolism Intestinal Mucosa/metabolism Mice Mice, Transgenic Organ Specificity Plants/chemistry Stomach/drug effects
Chemicals
Arnt protein, mouse Hif1a protein, mouse Hypoxia-Inducible Factor 1, alpha Subunit Aryl Hydrocarbon Receptor Nuclear Translocator Cytochrome P-450 CYP1A1
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Ito Shinji
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Chen Chi
Satoh Junko
Yim Sunhee
Gonzalez Frank J
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI31647
Published
2007-07-00
Pages
1940-50
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC1890999
Subset
IM
Grants
Intramural NIH HHS · United States
External Links
PubMed source DOI: 10.1172/JCI31647 PMC Full Text View journal details
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