TY - JOUR
T1 - α-Naphthoflavone-induced CYP1A1 gene expression and cytosolic aryl hydrocarbon receptor transformation
AU - Santostefano, M.
AU - Merchant, M.
AU - Arellano, L.
AU - Morrison, V.
AU - Denison, M. S.
AU - Safe, S.
N1 - Copyright:
Copyright 2004 Elsevier B.V., All rights reserved.
PY - 1993
Y1 - 1993
N2 - α-Naphthoflavone (αNF) is a weak aryl hydrocarbon (Ah) receptor agonist and inhibits the induction of CYP1A1 gene expression by 2,3,7,8- tetrachlorodibenzo-p-dioxin. It has been suggested that the Ah receptor antagonist activity is due to the formation of αNF-cytosolic Ah receptor complexes that fail to undergo transformation. This hypothesis is consistent with data obtained in this and other studies using αNF concentrations from 10 to 1000 nM. However, 10 μM αNF exhibited Ah receptor agonist activity in several assays. Incubation of rat hepatic cytosol with 10 μM αNF caused transformation of the Ah receptor, as determined in a gel retardation assay using a 32P-labeled oligonucleotide containing a single dioxin-responsive element (DRE). Incubation of rat hepatoma (H-4-II E) cells with 10 μM αNF not only resulted in the induction of CYP1A1 mRNA levels but also increased chloramphenicol acetyltransferase activity from a DRE-containing chloramphenicol acetyltransferase reporter plasmid. Moreover, the DRE- transformed cytosolic Ah receptor complex liganded with either αNF or 2,3,7,8-tetrachlorodibenzo-p-dioxin did not undergo significant dissociation at 4°. These data confirm that αNF is an Ah receptor agonist and, based on the results of previous studies, exhibits partial antagonist activity via competition for receptor binding sites.
AB - α-Naphthoflavone (αNF) is a weak aryl hydrocarbon (Ah) receptor agonist and inhibits the induction of CYP1A1 gene expression by 2,3,7,8- tetrachlorodibenzo-p-dioxin. It has been suggested that the Ah receptor antagonist activity is due to the formation of αNF-cytosolic Ah receptor complexes that fail to undergo transformation. This hypothesis is consistent with data obtained in this and other studies using αNF concentrations from 10 to 1000 nM. However, 10 μM αNF exhibited Ah receptor agonist activity in several assays. Incubation of rat hepatic cytosol with 10 μM αNF caused transformation of the Ah receptor, as determined in a gel retardation assay using a 32P-labeled oligonucleotide containing a single dioxin-responsive element (DRE). Incubation of rat hepatoma (H-4-II E) cells with 10 μM αNF not only resulted in the induction of CYP1A1 mRNA levels but also increased chloramphenicol acetyltransferase activity from a DRE-containing chloramphenicol acetyltransferase reporter plasmid. Moreover, the DRE- transformed cytosolic Ah receptor complex liganded with either αNF or 2,3,7,8-tetrachlorodibenzo-p-dioxin did not undergo significant dissociation at 4°. These data confirm that αNF is an Ah receptor agonist and, based on the results of previous studies, exhibits partial antagonist activity via competition for receptor binding sites.
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M3 - Article
C2 - 8381508
AN - SCOPUS:0027509084
VL - 43
SP - 200
EP - 206
JO - Molecular Pharmacology
JF - Molecular Pharmacology
SN - 0026-895X
IS - 2
ER -