**Food Factors and Oxidative DNA Damage / DNA Repair Systems**

Takeshi Hirano1 and Kazuyoshi Tamae2 *1Department of Life and Environment Engineering, Faculty of Environmental Engineering, The University of Kitakyushu,* 

*2Division of Teacher Training, Faculty of Education and Culture, University of Miyazaki, Japan* 

### **1. Introduction**

546 Selected Topics in DNA Repair

Zhang, Y., Talalay, P., Cho, C. G., Posner, G. H., 1992. A major inducer of anticarcinogenic

Acad Sci U S A 89, 2399-2403.

protective enzymes from broccoli: isolation and elucidation of structure. Proc Natl

8-Oxoguanine (7, 8-dihydro-8-oxoguanine, abbreviated as 8-oxo-Gua), a form of oxidized guanine, is a mutagenic lesion formed spontaneously in the genomic DNA of aerobic organisms (Fig. 1) and by the actions of exogenous factors, such as ionizing radiation, chemical pollutants, heavy metals, food factors, and bacteria. 8-Oxo-Gua induces GC-to-TA transversion type point mutations [1]. Point mutations generated via oxidative DNA damage are involved in cancer development, because mutations are a common feature of human cancers. Therefore, 8-oxo-Gua is considered to be involved in carcinogenesis. In this context, studies of 8-oxo-Gua have significant implications for understanding the underlying mechanisms of mutation-associated diseases, including cancer [2]. Although 8 oxo-Gua is not necessarily the most abundant form of oxidative DNA damage, it has been the most extensively studied, because it is quite easily measured by a method utilizing HPLC coupled with electrochemical detection in laboratories [3, 4]. The presence of 8-oxo-Gua and 8-oxoadenine (8-oxo-Ade) in mutagenic oxidized DNA products has been extensively studied, and their frequencies of generation in mammalian DNA and degrees of mutagenicity are similar [5-8]. The relative focus-forming activity, which indicates the mutation inducibility, of 8-oxo-Gua and 8-oxo-Ade were reportedly ~1% [7, 8].

Fig. 1. Structure of 7, 8-dihydro-8-oxoguanine or 8-hydroxyguanine (8-OH-Gua). 8-Oxo-Gua is formed by hydroxylation of guanine at the C-8 position.

Extensive efforts have been made to clone the repair enzymes for 8-oxo-Gua. The first information was obtained from the studies of an enzyme, formamidopyrimidine DNA glycosylase (Fpg or MutM), which excises 8-oxo-Gua, 2, 6-diamino-4-hydroxy-5 formamidopyrimidine (FapyGua), and 4, 6-diamino-5-formamidopyrimidine (FapyAde)

Food Factors and Oxidative DNA Damage / DNA Repair Systems 549

components of alcoholic beverages (including wine) besides polyphenols may be

The evidence that not only wine but also spirits and beer have cancer-preventive effects prompted us to investigate the molecular mechanisms of these effects of alcohol consumption due to factors other than polyphenols. In fact, recent evidences have suggested that the protective effects of red wine on cancer or cardiovascular diseases were not a consequence of the anti-oxidant capacity of alcohol [35, 36]. Arendt et al. reported the reduction of DNA

In this context, we analyzed the 8-oxo-Gua accumulation level in DNA and its repair ability (8-oxo-Gua nicking activity and mouse OGG1 (mOGG1) expression) in the livers of mice treated with 3'-MeDAB, a well known hepato-carcinogen as described above, and / or ethanol, to examine the effects of alcohol consumption on carcinogenesis (Fig. 2A) [37]. The method used to determine the 8-oxo-Gua nicking activity was described elsewhere [38]. In the study, we found that 12% ethanol reduced the 3'-MeDAB-induced 8-oxo-Gua accumulation (Fig. 2B). Moreover, the 8-oxo-Gua repair activity showed a decreasing tendency in 3'-MeDAB-treated mouse livers with 12% ethanol administration, without any significant differences (Fig. 2C). The decrease in the 8-oxo-Gua repair activity seems to be a reasonable consequence of the lower 8-oxo-Gua levels. Since we speculated that OGG1 fragmentation was a key event for 3'-MeDAB-induced 8-oxo-Gua accumulation [22], we predicted that OGG1 fragmentation might be inhibited by ethanol intake, as in the inhibition of the increase in 8-oxo-Gua levels. However, 12% ethanol intake failed to inhibit the 3'- MeDAB-induced fragmentation of OGG1 (groups D, E, and F in Fig. 2D). The observations indicated that ethanol intake reduced 8-oxo-Gua accumulation, without affecting the function of OGG1. However, since other enzymes besides OGG1 can reportedly repair 8 oxo-Gua [39], we speculate that ethanol consumption might induce these 8-oxo-Gua repair

Coffee has been a quite popular beverage in many parts of the world for a long time. However, its effects on human health are not well understood. Some studies suggested that coffee consumption had preventive properties for metabolic diseases, such as type 2 diabetes [40, 41], or cancers, such as hepatocellular carcinoma [42, 43] and colorectal cancer [44, 45], through its content of potentially antimutagenic substances [46]. These findings led

On the other hand, some studies provided negative conclusions for the effects of coffee consumption on human health. A large cohort study in Sweden and Japan indicated that coffee consumption was not associated with the risk of colorectal cancer [47, 48]. Furthermore, another cohort study indicated that coffee consumption increased the risk of certain cancers, such as gastric cancer [49]. These carcinogenic actions of coffee were supported by evidence that coffee contained numerous substances, such as glyoxal, methylglyoxal, ethylglyoxal, propylglyoxal, diacetyl, and acetol, with potentially genotoxic and mutagenic properties [46, 49-51]. Although the polyphenols in beverages, such as green tea, black tea, and coffee, are antioxidant substances, a recent study indicated the production of hydrogen peroxide, a harmful molecule for living organisms, by polyphenol-rich beverages [52]. Therefore, although numerous studies have been performed, the effects of

to the hypothesis that coffee consumption lowers the risk of some types of cancers.

coffee consumption on human health have remained undefined.

damage as another mechanism of the cancer-preventive function of wine [35].

responsible for the beneficial effects on human health.

systems to reduce the 8-oxo-Gua level.

**4. Coffee and 8-oxo-Gua / OGG1** 

from the DNA of *Escherichia coli* [9]. This enzyme has an activity to process the resulting abasic (AP) site, by cleaving both the 3'- and 5'-phosphodiester bonds by successive β- and δ-eliminations [10-12]. In 1996, an Fpg homologue was identified in *Saccharomyces cerevisiae* [13, 14]. This was the first report of an 8-oxoguanine DNA glycosylase 1 (OGG1). In the following year, mammalian (human and other mammals) homologues of OGG1 were identified and cloned [15-21]. 8-Oxo-Gua is efficiently removed from DNA via the shortpatch base excision repair (BER) pathway initiated by OGG1.

Among the environmental factors that are related to human diseases, food factors have a large influence on human health. To understand the mechanisms of food-related carcinogenesis, the roles of 8-oxo-Gua have been investigated in relationship with food factors. In this review article, we will focus on and describe the relationship between food factors and 8-oxo-Gua / 8-oxo-Gua repair systems.
