Our daily exposure to a variety of common materials containing nickel such as coins, kitchen equipment and costume jewelry belies the highly carcinogenic and often toxic nature of many nickel compounds. In particular, amorphous nickel subsulfide (Ni3S2) and water soluble nickel sulfate (NiSO4) have both been linked to pulmonary and renal cancers in workers exposed from an industrial environment. The molecular basis of this carcinogenic activity has not been identified and awaits a more complete understanding of nickel's biochemical reactivity. Simple nickel(II) salts alone demonstrate little ability to modify DNA and proteins irreversibly. However, when nickel binds to strong donor ligands, the resulting complex may promote a number of biologically destructive reactions. Peptides and proteins represent the most significant class of such ligands available within a cell, and DNA-binding proteins are obvious candidates for mediating genomic damage. Preliminary data suggests that histones do indeed activate the oxidative chemistry of nickel and serve, along with bound DNA, as targets of modification. The significant expertise gained by this laboratory on the biomimetic reactions of nickel during the previous funding period will now be applied to describe the role of chromatin in nickel carcinogenesis. Efforts will focus on cross-linking reactions of DNA and histones that likely represent the most detrimental processes induced by nickel in the presence of biological oxidants. The origins of crosslinking will be identified by use of nucleosomes with homogeneous positional and rotational structures. Sequence and conformational determinants of this reaction will be examined by using natural variants in nucleosome assembly. Nickel salts also promote a variety of other harmful lesions which will be subject to concurrent investigation. Our broad characterization is designed to distinguish the range of mechanisms that are stimulated by nickel in vitro as a model of the potentially mutagenic processes in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM047531-06
Application #
6179409
Study Section
Special Emphasis Panel (ZRG1-MCHA (01))
Program Officer
Lewis, Catherine D
Project Start
1993-08-01
Project End
2003-05-31
Budget Start
2000-06-01
Budget End
2001-05-31
Support Year
6
Fiscal Year
2000
Total Cost
$203,046
Indirect Cost
Name
University of Maryland College Park
Department
Chemistry
Type
Schools of Earth Sciences/Natur
DUNS #
City
College Park
State
MD
Country
United States
Zip Code
20742