ToxSci Advance Access originally published online on December 13, 2008
Toxicological Sciences 2009 107(2):394-403; doi:10.1093/toxsci/kfn251
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Published by Oxford University Press 2008.
Metal Ions-Stimulated Iron Oxidation in Hydroxylases Facilitates Stabilization of HIF-1
Protein
* Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, Maryland 21702
Advanced Biomedical Computing Center, Advanced Technology Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland 21702
Environmental Protection Agency, Research Triangle Park, North Carolina 27711
1 To whom correspondence should be addressed at National Cancer Institute, Bldg. 538, Room 205 E, Frederick, MD 21701. Fax: (301) 402-1037. E-mail: salnikok{at}mail.nih.gov.
Received June 10, 2008; accepted November 25, 2008
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Abstract |
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The exposure of cells to several metal ions stabilizes HIF-1
protein. However, the molecular mechanisms are not completely understood. They may involve inhibition of hydroxylation by either substitution of iron by metal ions or by iron oxidation in the hydroxylases. Here we provide evidence supporting the latter mechanism. We show that HIF-1 stabilization in human lung epithelial cells occurred following exposure to various metal and metalloid ions, including those that cannot substitute for iron in the hydroxylases. In each case addition of the reducing agent ascorbic acid (AA)* abolished HIF-1 protein stabilization. To better understand the role of iron oxidation in hydroxylase inhibition and to define the role of AA in the enzyme recovery we applied molecular modeling techniques. Our results indicate that the energy required for iron substitution by Ni(II) in the enzyme is high and unlikely to be achieved in a biological system. Additionally, computer modeling allowed us to identify a tridentate coordination of AA with the enzyme-bound iron, which explains the specific demand for AA as the iron reductant. Thus, the stabilization of HIF-1 by numerous metal ions that cannot substitute for iron in the enzyme, the alleviation of this effect by AA, and our computer modeling data support the hypothesis of iron oxidation in the hydroxylases following exposure to metal ions.
Key Words: antioxidants; metals; transcription factors.
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