Induction of 1,N²‐etheno‐2′‐deoxyguanosine in DNA exposed to β‐carotene oxidation products

Abstract

Epidemiological studies testing the e¡ect of L L-carotene in humans have found a relative risk for lung cancer in smokers supplemented with L L-carotene. We investigated the reactions of retinal and L L-apo-8P P-carotenal, two L L-carotene oxidation products, with 2P P-deoxyguanosine to evaluate their DNA damaging potential. A known mutagenic adduct, 1,N 2 -etheno-2P P-deoxyguanosine, was isolated and characterized on the basis of its spectroscopic features. After treatment of calf thymus DNA with L L-carotene or L L-carotene oxidation products, signi¢-cantly increased levels of 1,N 2 -etheno-2P P-deoxyguanosine and 8-oxo-7,8-dihydro-2P P-deoxyguanosine were quanti¢ed in DNA. These lesions are believed to be important in the development of human cancers. The results reported here may contribute toward an understanding of the biological e¡ects of L L-carotene oxidation products. ß

Genotoxic Effects of Carotenoid Breakdown Products in Human Retinal Pigment Epithelial Cells

“…The genotoxic effects of β-carotene (20 µM) and BA8C (2, 5, and 20 µM) have been demonstrated in A549 cells29. Moreover, BA8C is also demonstrated to form 1, N 2 –etheno-2’-deoxyguanosine adduct which could lead to DNA strand breaks and mutations42. These results are concordant with our findings which show significant DNA damage in ARPE-19 cells treated with similar concentrations of LBP and BA8C.…”

Inhibition of Proliferation and Induction of Apoptosis by the Combination of β-carotene and 1,25-dihydroxyvitamin D3 in Human Esophageal Cancer EC9706 Cells

“…Eisman reported 1,25-dihydroxyvitamin D 3 receptor existed in human breast cancer cells firstly, which inspired people to explore the anti-cancer effect of vitamin D (Eisman et al, 1986). But the excessive β-carotene may lead the body to a high oxidation state (Marques et al, 2004), which harmful to health, and while 1,25-dihydroxyvitamin D 3 is a promising material with anti-tumor activity, excessive 1,25-dihydroxyvitamin D 3 could also easily induce hypercalcemia (Iqbal et al, 2003). β-carotene and 1,25-dihydroxyvitamin D 3 in combination could not only reduce the amount of β-carotene, but also reduce the amount of 1,25-dihydroxyvitamin D 3 , thus reducing their pharmaceutical concentration, their toxic effects and the resistance of tumor cells, so the combination of these two agents is a new research direction of prevention and treatment of cancer.…”

Site Specific Synthesis and Polymerase Bypass of Oligonucleotides Containing a 6-Hydroxy-3,5,6,7-tetrahydro-9H-imidazo[1,2-a]purin-9-one Base, an Intermediate in the Formation of 1,N2-Etheno-2‘-deoxyguanosine

“…Further support of the dehydration/hydration pathway comes from previous work on the related 1,N 2 -glyoxal adduct of Gua. The C6-hydroxyl group of this adduct (19) was shown to quantitatively exchange with alcohol solvent to give the 6-alkoxy derivative (20), a process that would most likely occur through an imine or iminium ion intermediate (Scheme 5) (56). When the glyoxal or 6-alkoxy derivative was treated with NaB(CN)H 3 , reduction at the C6-position occurred to give the 7-hydroxyethano or the N 2 -(2-hydroxyethyl) derivatives (21 and 22, Scheme 5).…”

“…In addition, background levels of etheno adducts have been found in unexposed populations (13). The endogenous C 2 donors are believed to arise from oxidative damage to unsaturated fatty acids, namely, 2,3-epoxyaldehydes, although other lipid peroxidation products have also been shown to form etheno adducts (14)(15)(16)(17)(18)(19).…”