Bulky endogenous DNA modifications (I-compounds) - possible structural origins and functional implications

I-compounds are bulky covalent DNA modifications which increase with age in tissues of unexposed laboratory animals and are derived from endogenous DN A-reactive intermediates of nutrient and oxygen metabolism. They have been classified into 2 major groups, i.e., type I and type II. Profiles and leve ls of type I I-compounds show considerable variation depending on species, strain, tissue, and gender, but are also affected by diet and chemical and hormonal exposures, indicating their formation to be determined by genetic and environmental factors. For example, sex hormones, dietary oat lipids, a nd isoprenoids affect their profiles and/or levels in tissue DNA. A gradual depletion of many type I I-compounds occurs during carcinogenesis, as many carcinogens/tumor promoters significantly reduce their levels, and neoplas ms display very low levels, apparently independent of growth rate, indicati ng a loss of the ability to form these modified nucleotides. Conversely, di etary restriction, the most effective method to retard carcinogenesis and a ging, significantly elevates type I I-compound levels, as compared to age-m atched ad libitum-fed animals. Levels of many Liver and kidney I-compounds exhibit genotype and diet-dependent positive linear correlations with media n life span. Formation of high levels of oat-related type I I-compounds has been associated with reduced formation of carcinogen-induced preneoplastic hepatic foci. These results suggest that such DNA modifications may not re present DNA lesions but may rather be functionally important. This view is supported by circadian rhythms displayed by some I-compounds. Thus, certain type I I-compounds may play a protective role against carcinogenesis and a ge-associated degenerative processes. Type II I-compounds, on the other han d, represent DNA damage and include several bulky lesions, which are enhanc ed by pro-oxidant carcinogens such as ferric nitrilotriacetate (Fe-NTA) in target organ (kidney) DNA of rodents and are identical to products generate d by oxidizing DNA or oligonucleotides under Fenton reaction conditions in vitro. Some of these products appear to be base-base or base-sugar intrastr and crosslinks. Notably, Fe-NTA reduces the levels of type I I-compounds in renal DNA. Type II I-compound levels are increased in tissue DNA of normal newborn rats. The formation of oxidative DNA lesions in neonates is most l ikely caused by oxidative stress associated with the sudden increase of par tial oxygen pressure in arterial blood and tissues at birth. In view of the rapid cell replication at this developmental stage, endogenous oxidative D NA lesions sustained early in life may contribute to the development of can cer and degenerative diseases Inter in life. (C) 1999 Elsevier Science B.V. All rights reserved.