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ToxSci Advance Access originally published online on November 13, 2007
Toxicological Sciences 2008 102(1):120-128; doi:10.1093/toxsci/kfm281
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

PPAR{alpha} and PPARβ Are Differentially Affected by Ethanol and the Ethanol Metabolite Acetaldehyde in the MCF-7 Breast Cancer Cell Line

Nagaraj Gopisetty Venkata, Cho S. Aung, Peter J. Cabot, Gregory R. Monteith and Sarah J. Roberts-Thomson1

School of Pharmacy, The University of Queensland, Brisbane, Queensland 4072, Australia

1 To whom correspondence should be addressed at School of Pharmacy, Steele Building (03), The University of Queensland, Brisbane, Queensland 4072, Australia. Fax: +61-7-3365-1688. E-mail: sarahrt{at}uq.edu.au

Received October 3, 2007; accepted October 30, 2007


  Abstract

The activity and/or the level of the peroxisome proliferator–activated receptors (PPARs) in liver and oligodendrocytes are regulated by ethanol. Despite the association between ethanol consumption and breast cancer risk, and the increasing evidence for an involvement of PPARs in some cancers, there have been no studies on the effect of ethanol or its metabolite acetaldehyde on PPARs in breast cancer. Using the MCF-7 breast cancer cell line, we examined the relationship between ethanol and its metabolite acetaldehyde on PPAR{alpha} and PPARβ transactivation. Ethanol (20mM) reduced the potency of the PPARβ ligand GW0742, evident by a rightward shift in the GW0742 dose-response curve, whereas for PPAR{alpha} activation by GW7647, ethanol mediated its effects primarily through reducing efficacy as evidenced by a reduction in maximal response. Using the enzyme inhibitors 4-methylpyrazole and cyanamide and the metabolite acetaldehyde, we showed that PPAR{alpha} and PPARβ are differentially modulated by ethanol and acetaldehyde. While acetaldehyde is responsible for the inhibition of PPAR{alpha} ligand inhibition with a concentration that inhibits 50% of activity (IC50) of 111 nM, acetaldehyde has no effect on PPARβ or its ligand activation. Instead, inhibition of PPARβ transactivation is mediated directly by ethanol. The differential effect of ethanol and acetaldehyde on PPAR{alpha} and PPARβ further underscores the differences between these receptors and may indicate the relevance of PPARs in the effects of ethanol in the human breast.

Key Words: ethanol; acetaldehyde; PPAR; proliferation; breast; cell lines; MCF-7.


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