Nickel carcinogenesis, mutation, epigenetics, or selection.

Abstract

Exposure ofcells to carcinogenic nickel compounds induces many genes that are commonly expressed in cancer cells but not in normal cells.Nickel Carcinogenesis, Mutation, Epigenetics, or Selection Nickel compounds have been well established as human carcinogens. Investigations into the molecular mechanisms of nickel carcinogenesis have revealed that not all nickel compounds are equally carcinogenic: certain water-insoluble nickel compounds exhibit potent carcinogenic activity, whereas highly water-soluble nickel compounds exhibit less potency (1). The reason for the high carcinogenic activity of certain water-insoluble nickel compounds relates to their bioavailability and the ability of the nickel ions to enter cells and reach chromatin. The water-insoluble nickel compounds enter cells quite efficiently via phagocytic processes, and subsequent intracellular dissolution yields very high cellular levels of Ni2+. Mathematical estimations indicated that if a 1.45-pm nickel sulfide particle totally dissolved in a cell, the potential nickel concentration would be 250 mM, and if a 4.0-pm nickel sulfide particle totally dissolved in a cell, the potential nickel concentration would be 4.75 M. Thus, the process of phagocytosis represents a very efficient manner for the accumulation of nickel inside the cell.Nickel is classified as a borderline metal ion because it has both soft and hard metal properties and it can bind to sulfur, nitrogen, and oxygen groups. Nickel ions are very similar in structure and coordination properties to magnesium. Like magnesium, nickel binds to the oxygen of the DNA phosphate backbone; but like copper and cobalt, nickel enjoys a high affinity for the imidazole nitrogen of histidine in proteins.

Epigenetics and Cancer

“…In the field of carcinogenesis research, there is growing awareness that neoplastic transformation must be viewed as an environmental process. 11 Breivik and Gaudernack have addressed this issue and presented a model that integrates evolution and carcinogenesis at the molecular level. 12,13 This model offers new perspectives (including epigenetics) to carcinogenesis, and relates the neoplastic process to the basic evolutionary concept of biology.…”

“…Within the epigenetic effects, alteration in the levels of transcription factors, such as ATF-1, p53, HIF-1, HIF-1alpha, and NFk have been observed. 11 The relationship between nickel and calcium metabolism and the role it plays in nickel carcinogenesis has also been considered. These epigenetic events have been discussed with respect to the effects that nickel has on inducing DNA methylation in cells.…”

Protective role of l-ascorbic acid on antioxidant defense system in erythrocytes of albino rats exposed to nickel sulfate

“…The difference in the toxicity across compounds is probably due to ability of water-soluble nickel compounds to cross the cell membrane and interact with cytoplasmic protein (ATSDR 2003). It is well known that the toxicitiy due to nickel exposure by inhalation is much complicated by the fact that inhaled insoluble nickel compounds inside the lung for long times and give rise to high local concentration with corresponding severe irreversible effects (Dunnick et al 1995;Costa & Klein, 1999). It is well established that rapidity of toxic effects, exerted by heavy metals is related to blood's transport function, with the blood distributing the metals to all the body parts.…”

The Octapeptidic End of the C-Terminal Tail of Histone H2A Is Cleaved Off in Cells Exposed to Carcinogenic Nickel(II)

“…The mechanistic concepts in nickel carcinogenesis include promutagenic DNA damage (2) and epigenetic effects in chromatin (3,4) resulting from Ni(II) binding to the cell nucleus (5). Full understanding of intracellular Ni(II) reactivity is crucial for the design of preventative and therapeutic measures.…”