Just to be contrary....
J Pharmacol Exp Ther. 2010 Aug 17. [Epub ahead of print]
Estrogen receptor expression is required for low-dose resveratrol mediated repression of aryl hydrocarbon receptor activity.
Perdew GH,
Hollingshead BD,
Dinatale BC,
Morales JL,
Labrecque MP,
Takhar MK,
Tam KJ,
Beischlag TV.
1 The Pennsylvania State University;
FREE TEXT
Abstract
The putative cardio-protective and chemo-preventive properties of the red wine phenolic resveratrol (RES) have made it the subject of a growing body of clinical and basic research. We have begun investigations focusing on the effects of RES on the activity of the aryl hydrocarbon receptor complex.
Our evidence suggests that RES is a potent repressor of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) inducible gene transcription in estrogen receptor-positive human breast, lung and colon cancer cell lines. RES activates the transcription of the estrogen receptor target genes to the same degree as estradiol (E2) in human MCF-7 breast cancer cells. Unlike E2, which can only diminish TCDD-inducible CYP1A1 gene transcription by approximately 50%, RES can completely abrogate this response. Furthermore, 50% repression of TCDD-inducible transcription can be achieved with 100 nM RES, approximately 2.5 orders of magnitude lower than concentrations required for maximal inhibition, suggesting that multiple mechanisms are responsible for this effect. RES (100 nM) does not prevent ligand binding of a TCDD analogue nor does it prevent AHR from binding to its response element in the 5' regulatory region of the CYP1A1 gene. Small inhibitory RNAs directed to ERalpha have demonstrated that RES-mediated repression of CYP1A1 is dependent on ERalpha. While CYP1A1 protein levels in MCF-7 cells are refractory to the low dose transcriptional effects of RES, a concomitant decrease in CYP1A1 protein levels are observed in Caco-2 cells. These
results highlight a low-dose RES effect that could occur at nutritionally relevant exposures and are distinct from the high dose effects often characterized.
PMID: 20716622 [PubMed - as supplied by publisher]Free Article
Quote:
RES is marketed commercially as a nutritional supplement and as a preventive medicine (Jang et al., 1997; Kundu and Surh, 2004). However, the effects of RES most often studied, namely those mediated by NF-κB, AP-1 and sirtuins and other targets are realized at concentrations (30-100 μM) well in excess of those reasonably achievable even by the over consumption of concentrated dietary supplements. Thus, the mechanisms responsible for the chemo-protective properties of resveratrol observed in dietary studies remain to be determined.
Mean peak plasma concentrations in humans range from the pico-molar to mid-nanomolar after oral ingestion of quantities associated with normal dietary consumption and reach the low micromolar range only after consumption of gram quantities [for review see (Cottart et al.)].
|
Quote:
ablation of ERα expression appears to indicate that ERα is the primary target of RES
at nanomolar concentrations in these studies. In addition, these findings indicate that RES concentrations as low as 5 nM may have significant chemo-protective properties.
|
Quote:
In conclusion, we have documented the repression of ligand inducible AHR signaling by concentrations of RES well below those attributed to either the pharmacological antagonism of the receptor or the widely reported activation of other cellular constituents such as sirtuins.
Furthermore, we have established that ERα is a target for low dose exposure to RES. The data presented here provides a plausible explanation for some of the chemo-preventive effects of dietary consumption of RES-containing foodstuffs.
|