Searches for ultimate chemical carcinogens and their reactions with cellular macromolecules

Abstract

Studies on a variety of chemical carcinogens have demonstrated that their ultimate reactive and carcinogenic forms are strong electrophiles. Some carcinogens, such as alkylating agents, are in their ultimate forms as administered, but most require metabolism to these active derivatives. The ultimate carcinogens react, usually non-enzymatically, with nucleophilic constituents in vivo. Of particular interest in regard to their possible importance in carcinogenesis have been the covalent interactions of these electrophilic reactants with cellular informational macromolecules, the DNAs, RNAs, and proteins. Current data are consistent with the idea that the initiation step of chemical carcinogenesis is a mutagenic event and is caused by alteration of DNA by the ultimate carcinogens. The nature of the carcinogen metabolite(s) involved in the promotion phase has not been determined, but there appears to be no requirement that they be electrophilic. The development of the concept of ultimate chemical carcinogens as strong electrophilic reactants is reviewed, especially with respect to the studies carried in the authors' laboratory.

Formaldehyde-induced toxicity in the nasal epithelia of workers of a plastic laminate plant

“…Apart from the potential value of the nasal epithelial cells for the prediction of cancer risk of the respiratory tract, 16,27 the use of nasal epithelia may allow mechanistic studies of various carcinogens, including those contained in tobacco smoke, 16,39 industrial air pollution, [20][21][22]28 and hair-dyeing. 49 Additionally, the patterns of Phase I enzymes that have an important role in the production of ROS during the metabolism of a number of carcinogens 50 are qualitatively different in the respiratory tract than in other tissues. 51 As previously mentioned, the levels of M 1 dG adducts were measured in the nasal epithelia to investigate the molecular mechanisms in the target site for FA-induced nasal carcinogenesis, since the formation of DNA damage in this region reflects the genotoxic action of FA as well as the actions of mediators released from the nasal epithelial cells following the inhalation of this compound.…”

Prostate cancer risk from occupational exposure to polycyclic aromatic hydrocarbons interacting with the GSTP1 Ile105Val polymorphism

“…PAH are ubiquitous environmental contaminants that result from incomplete combustion processes and are known carcinogens [8]. PAH are thought to exert their carcinogenic properties through their ability to form PAH-DNA adducts [9][10][11]. Both casecontrol [12] and cohort [13] studies have found that most jobs associated with occupational PAH exposure have the potential for prostate cancer.…”

DNA adduct formation and 7-ethoxyresorufin O-deethylase induction in primary culture of rainbow trout hepatocytes exposed to benzo[a]pyrene

“…Among molecular targets of xenobiotics, interest has been focused on DNA, since DNA-xenobiotic binding is considered to be a critical step that may initiate mutagenesis and carcinogenesis (Miller and Miller, 1981). Xenobiotics may interact with DNA either directly or after transformation by metabolizing enzymes into reactive species that react with DNA forming DNA addition products (DNA adducts).…”