Dietary phytochemicals regulate whole-body CYP1A1 expression through an arylhydrocarbon receptor nuclear translocator-dependent system in gut
J Clin Invest. 2007 Jul;117(7):1940-50. doi: 10.1172/JCI31647.
Shinji Ito 1 , Chi Chen, Junko Satoh, Sunhee Yim, Frank J Gonzalez
1 Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
DOI: 10.1172/JCI31647
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.
Active Transport, Cell Nucleus
Aryl Hydrocarbon Receptor Nuclear Translocator / genetics
Aryl Hydrocarbon Receptor Nuclear Translocator / metabolism*
Cytochrome P-450 CYP1A1 / genetics
Cytochrome P-450 CYP1A1 / metabolism*
Diet*
Epithelium / metabolism
Gastric Mucosa / metabolism*
Gene Expression Regulation, Enzymologic / drug effects*
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Intestinal Mucosa / metabolism
Organ Specificity
Plants / chemistry*
Stomach / drug effects*
Arnt protein, mouse
Hif1a protein, mouse
Hypoxia-Inducible Factor 1, alpha Subunit
Aryl Hydrocarbon Receptor Nuclear Translocator
Cytochrome P-450 CYP1A1