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ToxSci Advance Access published online on November 13, 2007
Toxicological Sciences, 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 PPARß 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-Thomson

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

Corresponding author: Sarah J Roberts-Thomson, School of Pharmacy, Steele Building (03), The University of Queensland, Brisbane, QLD, 4072, Australia, Ph: +61 7 3365 3193, Fax: +61 7 3365 1688, E-mail: sarahrt{at}uq.edu.au

Received October 3, 2007; revision received October 29, 2007; accepted October 30, 2007


  Abstract

The activity and/or 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 PPARß transactivation. Ethanol (20 mM) reduced the potency of the PPARß 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 PPARß are differentially modulated by ethanol and acetaldehyde. While acetaldehyde is responsible for the inhibition of PPAR{alpha} ligand-activation with an IC50 of 111 nM, acetaldehyde has no effect on PPARß or its ligand-activation. Instead inhibition of PPARß transactivation is mediated directly by ethanol. The differential effect of ethanol and acetaldehyde on PPAR{alpha} and PPARß 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.

n.gopisettyvenkata{at}uq.edu.au, c.aung{at}uq.edu.au, p.cabot{at}uq.edu.au, gregm{at}uq.edu.au, sarahrt{at}uq.edu.au


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