Endogenous genotoxic agents and processes as a basis of spontaneous carcinogenesis

Abstract

SummaryA list ofendogenaus DNA·damaging agents and processes is given. Endogenaus e/ectrophiles are found with the cosubstrates of physiological transfer reactions (S-adenosylrnethionine for methylation, A TP 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 endogenaus nitrose 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 endogenaus hydrogen peroxide, and the formation of lipid peroxides. Genetic instability by spontaneaus deaminations and depurinations as well as replicative instability by tautomer errors andin the presence of mutagenic metal ions represent a third important dass of endogenaus genotoxic processes. The postulated endogenaus 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 endogenaus DNA damage. The presence of endogenaus DNA darnage implies that exogenaus DNAcarcinogen adducts give rise to an incremental darnage which is expected to be proportional to the carcinogen dose at lowest Ievels. An increased tumor risk due to exposure to exogenaus genotoxic carcinogens could therefore be assessed in terms of the background DNA damage~ for instance in multiples of the mean Ievel or of the interindividual variability in a population. bind covalently to DNA of target cells. If these DNA-carcinogen adducts are not repaired before the DNA replicates, a mutation in a daughter strand can result. lf this occurs in a critical gene, a heritable step towards malignant transformation· of the cell could be taken. In an attempt to correlate carcinogenic potency with genotoxic potency (Lutz, 1979), a number of carcinogens were identified which did not bind covalently to 0165-1110/90/$03.50

Generation of an endogenous DNA-methylating agent by nitrosation in Escherichia coli

“…The nature of this endogenous DNA-methylating agent is unknown. Putative candidates or sources of such agents include S-adenosylmethionine (SAM), lipid peroxidation, and amine nitrosation (27). SAM, a methyl group donor in enzymatic DNA methylation reactions in vivo, is also a weak nonenzymatic DNA-methylating agent in vitro (4,37).…”

Dose-response relationship for chemical carcinogenesis by genotoxic agents

“…In centrast to this view is the understanding the DNA is constantly being damaged by endogenaus and unavoidable agents and processes 8 • F or instance, endogenaus electrophiles are found with the CO-substrates of physiological transfer reactions (e.g., S-adenosyl-· MAX.…”

Topics in cancer risk assessment.

“…For DNA-reactive carcinogens, it has been argued that their additivity to the background rate of ongoing carcinogenic processes predicts that the dose-response curve will be linear at low doses (59-61). Lutz (62) argued that "the presence of endogenous DNA damage implies that exogenous DNA-carcinogen adducts give rise to an incremental damage that is expected to be proportional to the carcinogen dose at the lowest levels." This, of course, says nothing about the doseresponse relationship at higher doses where curvature may occur due to saturation of critical metabolic pathways or DNA repair mechanisms, or where cytotoxicity may occur or cell proliferation may be induced (31,(63)(64)(65)(66)(67)(68).…”