title: Aryl hydrocarbon receptor repressor (AhRR) function revisited: repression of CYP1 activity in human skin fibroblasts is not related to AhRR expression.
abstract: The skin reacts to environmental noxae by inducing cytochrome P450 (CYP)-catalyzed reactions via activation of the aryl hydrocarbon receptor (AhR). A drawback of this response is the generation of oxidative stress, which is especially dangerous for postreplicative cells such as dermal fibroblasts, in which damage may accumulate over time. Accordingly, in dermal fibroblasts, CYP1 expression is repressed and it has been proposed that this is due to the AhR repressor (AhRR), which is supposedly overexpressed in fibroblasts as compared with other skin cells. Here, we revisited this "AhRR hypothesis", which has been mainly based on ectopic overexpression studies and correlation analyses of high AhRR gene expression with CYP1A1 repression in certain cell types. In primary human skin fibroblasts (NHDFs) of 25 individuals, we found that (i) the AhRR was expressed only at moderate RNA copy numbers and that, against the common view, (ii) in some fibroblast strains, CYP1A1 mRNA expression could be induced by AhR activators. However, even the highest induction did not translate into measurable CYP1 enzyme activity, and neither basal expression nor mRNA inducibility correlated with AhRR expression. In addition, enhancement of CYP1A1 mRNA expression by trichostatin A, which inhibits AhRR-recruited histone deacetylases at the CYP1A1 promoter, failed to induce measurable CYP1 activity. Finally, AhRR-deficient ((-/-)) mouse embryonic fibroblasts were not induced to biologically relevant CYP1 enzyme activity despite impressive mRNA induction. These data clearly indicate that repressed CYP1 activity in NHDFs is not causally related to AhRR expression, which may serve a different, yet unknown, biological function.
authors.affiliation: IUF-Leibniz Research Institute for Environmental Medicine, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Tigges
authors.forename: Heike
authors.initials: H
authors.lastname: Weighardt
authors.forename: Sandra
authors.initials: S
authors.lastname: Wolff
authors.forename: Christine
authors.initials: C
authors.lastname: Götz
authors.forename: Irmgard
authors.initials: I
authors.lastname: Förster
authors.forename: Zippora
authors.initials: Z
authors.lastname: Kohne
authors.forename: Ulrike
authors.initials: U
authors.lastname: Huebenthal
authors.forename: Hans F
authors.initials: HF
authors.lastname: Merk
authors.forename: Josef
authors.initials: J
authors.lastname: Abel
authors.forename: Thomas
authors.initials: T
authors.lastname: Haarmann-Stemmann
authors.forename: Jean
authors.initials: J
authors.lastname: Krutmann
authors.forename: Ellen
authors.initials: E
authors.lastname: Fritsche
mesh_terms: D000328:Adult; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis*; D001564:Benzo(a)pyrene / Q000494:pharmacology; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists; D012097:Repressor Proteins / Q000096:biosynthesis*; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D055815:Young Adult
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001564:Benzo(a)pyrene; D019363:Cytochrome P-450 CYP1A1; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008748:Methylcholanthrene; D018336:Receptors, Aryl Hydrocarbon; D012097:Repressor Proteins; C492162:AHRR protein, human; C012589:trichostatin A