Molecular models in nickel carcinogenesis

Nickel compounds are known human carcinogens, but the exact molecular mecha nisms of nickel carcinogenesis are not known. Due to their abundance, histo nes are likely targets for Ni(II) ions among nuclear macromolecules. This p aper reviews our recent studies of peptide and protein models of Ni(II) bin ding to histones. The results allowed us to propose several mechanisms of N i(II)-inflicted damage, including nucleobase oxidation and sequence-specifi c histone hydrolysis. Quantitative estimations of Ni(II) speciation, based on these studies, support the likelihood of Ni(II) binding to histones in v ivo, and the protective role of high levels of glutathione. These calculati ons indicate the importance of histidine in the intracellular Ni(II) specia tion. (C) 2000 Elsevier Science Inc. All rights reserved.