Involvement of a post-transcriptional mechanism in the inhibition of CYP1A1 expression by resveratrol in breast cancer cells

Resveratrol decreases basal and induced CYP1AI mRNA/protein levels in both in vitro and in vivo models, and some studies suggest that resveratrol acts as an aryl hydrocarbon receptor (AhR) antagonist. Treatment of T47D or MCF-7 cells with 10 muM resveratrol inhibited induction of CYP1AI mRNA and CYP1AI-dependent activity after treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), as previously reported. In contrast, resveratrol did not inhibit TCDD-induced reporter gene activity in cells transfected with an Ah-responsive construct containing a human CYP1AI gene promoter insert, whereas 3'-methoxy-4'-nitroflavone, a "pure" AhR antagonist, inhibited this response. Resveratrol induced transformation of the rat cytosolic AhR and, after treatment of T47D and MCF-7 cells with resveratrol, a transformed nuclear AhR complex was observed. In contrast to 3'-methoxy-4'-nitroflavone, resveratrol did not block TCDD-induced AhR transformation in vitro or nuclear uptake of the AhR complex in breast cancer cells. Thus, the action of resveratrol on the AhR was consistent with that of an AhR agonist; however, resveratrol did not exhibit functional AhR agonist or antagonist activities in breast cancer cells. Actinomycin D chase experiments in T47D cells showed that resveratrol. and dehydroepiandrosterone both increased the rate of CYP1AI mRNA degradation, whereas resveratrol did not affect CYP1AI-dependent activity in cells pretreated with TCDD for 18 hr. These data suggest that resveratrol inhibits CYP1AI via an AhR-independent post-transcriptional pathway. (C) 2001 Elsevier Science Inc. All rights reserved.