Endogenous genotoxic agents and processes as a basis of spontaneous carcinogenesis

Abstract

A list of endogenous DNA-damaging agents and processes is given. Endogenous electrophiles are found with the cosubstrates of physiological transfer reactions (S-adenosylmethionine for methylation, ATP for phosphorylation, NAD+ for ADP-ribosylation, acetyl CoA for acetylation). Aldehyde groups (glyceraldehyde-3-phosphate, formaldehyde, open forms of reducing sugars, degradation products of peroxidation) or alkylating degradation products derived from endogenous nitroso compounds represent additional possibilities. Radical-forming reactions include leakage of the superoxide anion radical from terminal cytochromes and redox cycles, hydroxyl radical formation by the Fenton reaction from endogenous hydrogen peroxide, and the formation of lipid peroxides. Genetic instability by spontaneous deaminations and depurinations as well as replicative instability by tautomer errors and in the presence of mutagenic metal ions represent a third important class of endogenous genotoxic processes. The postulated endogenous genotoxicity could form the mechanistic basis for what is called 'spontaneous' tumor incidence and explain the possibility of an increased tumor incidence after treatment of animals with non-genotoxic compounds exhibiting tumor-promoting activity only. Individual differences are expected to be seen also with endogenous DNA damage. The presence of endogenous DNA damage implies that exogenous DNA-carcinogen adducts give rise to an incremental damage which is expected to be proportional to the carcinogen dose at lowest levels. An increased tumor risk due to exposure to exogenous genotoxic carcinogens could therefore be assessed in terms of the background DNA damage, for instance in multiples of the mean level or of the interindividual variability in a population.