Etheno DNA-base adducts from endogenous reactive species

Promutagenic etheno (epsilon) adducts in DNA are generated through reaction s of DNA bases with LPO products derived from endogenous sources or from ex posure to several xenobiotics. The availability of sensitive methods has ma de it possible to detect three epsilon-adducts in vivo, namely epsilon dA, epsilon dC and N-2,3-epsilon dG. One probable endogenous source for the for mation of these adducts arise a from LPO products such as trans-4-hydroxy-2 -nonenal (HNE), resulting in highly variable background E-adduct levels in tissues from unexposed humans and rodents. The range of background levels o f epsilon dA X 10(-8)dA detected inhuman tissues was < 0.05 to 25 and in ro dent tissues 0.02 to 10; the corresponding values for epsilon dC x 10(-8) d C were 0.01 to 11 and 0.03 to 24, respectively. Part of this variability ma y be associated with different dietary intake of antioxidants and/or omega- 6 PUFAs which oxidize readily to form 4-hydroxyalkenals, as epsilon dA and epsilon dC levels in WBC-DNA of female volunteers on a high omega-6 PUFA di et were drastically elevated. Increased levels of etheno adducts were also found in the liver of cancer-prone patients suffering from hereditary metal storage diseases, i.e., Wilson's disease (WD) and primary hemochromatosis (PH) as well as in Long-Evans Cinnamon rats, an animal model for WD. Increa sed metal-induced oxidative stress and LPO-derived epsilon-adducts, along w ith other oxidative damage, may trigger this hereditary liver cancer. epsil on-Adducts could hence be explored as biomarkers (i) to ascertain the role of LPO mediated DNA damage in human cancers associated with oxidative stres s imposed by certain lifestyle patterns, chronic infections and inflammatio ns, and (ii) to verify the reduction of these epsilon-adducts by cancer che mopreventive agents. This article summarizes recent results on the formatio n, occurrence and possible role of E-DNA adducts in carcinogenesis and muta genesis. (C) 1999 Elsevier Science B.V. All rights reserved.