Aryl hydrocarbon receptor deficient mice (Ahr-/-) exhibit an accumulation of liver retinylpalmitate

F. Andreola, P. Fernandez-Salguero, F. J. Gonzalez, Luigi M. De Luca

Research output: Contribution to journalArticle

Abstract

Carcinogens cause squamous metaplasia of epithelial tissues and reduce liver and/or blood retinoid content. However, the mechanism for these effects is presently unknown. Recently, a mouse line lacking expression of Ahr (Ahr-/-) has been generated that allowed us to address the potential role of the Ahr in the metabolism of retinoids. HPLC analysis of liver ethanolic extracts showed a gene dosage effect on the concentration of retinylpalmitate (RP). RP levels were 2 and 3.2 times higher in Ahr-/- than in heterozygous (Ahr+/-) and wildtype (Afir+/+) controls, respectively. To explain this accumulation of RP, we investigated retinoic acid (RA) metabolism in microsomes from livers of each genotype. Ahr-/- mice could not metabolize RA as efficiently as Ahr+/and Ahr+/+, either stimulated or not by TCDD. RA metabolism was studied in vaccinia expressed CYP1A1 and CYP1A2. Neither cytochrome was able to metabolize RA. Since aldehyde dehydrogenases 1 and 2 (Adh1, Adh2) are involved in RA synthesis, we investigated the expression of their transcripts by Northern blot analysis. A marked reduction (8 to 10 fold) in the expression of Adh2 was found in Ahr -/- mice vs +/- and +/+ mice. These data suggest that the increase in liver RP in -/- and +/- mice is the result of reduced RA synthesis and catabolism. These findings establish the first molecular connection between a carcinogen receptor and vitamin A.

Original languageEnglish (US)
Pages (from-to)A440
JournalFASEB Journal
Volume11
Issue number3
StatePublished - Dec 1 1997
Externally publishedYes

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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