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Supplement: Proceedings of the Fourth International Scientific Symposium on Tea and Human Health

Green Tea Consumption Is Associated with Decreased DNA Damage among GSTM1-Positive Smokers Regardless of Their hOGG1 Genotype^1–3,

⁴ Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ 85724 and ⁵ Arizona Cancer Center, Tucson, AZ 85724

^* To whom correspondence should be addressed. E-mail: ihakim{at}email.arizona.edu.

	ABSTRACT

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
The levels of tobacco-related DNA adducts in human tissues reflect a dynamic process that is dependent on the intensity and time of exposure to tobacco smoke, the metabolic balance between activation of detoxification mechanisms, and the removal of adducts by DNA repair and/or cell turnover. Urinary 8-hydroxydeoxyguanosine (8-OHdG) is probably 1 of the most abundant DNA lesions formed during oxidative stress and is proposed as a sensitive biomarker of the overall oxidative DNA damage and repair. We performed this study to determine whether there were differences in increased oxidative stress susceptibility to smoking within the combined GSTM1 and hOGG1 genotypes and the impact of green tea drinking on this. We completed a Phase II randomized, controlled, 3-arm tea intervention trial to study the effect of high consumption of decaffeinated green or black tea or water on urinary 8-OHdG among heavy smokers and to evaluate the roles of GSTM1 and hOGG1 genotypes as effect modifiers. Assessment of urinary 8-OHdG after adjustment for baseline measurements and other potential confounders revealed a significant effect of green tea consumption (P = 0.001). The change from baseline was significant in all GSTM1-positive smokers regardless of their hOGG1 genotype. Our data show that consumption of 4 cups (960 mL) of tea/d is a feasible and safe approach and was associated with a significant decrease in urinary 8-OHdG among green tea consumers. Our finding also suggests that green tea intervention might be effective in decreasing DNA damage in the subgroup of smokers who are GSTM1 positive regardless of their hOGG1 genotype.

	Introduction

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

Although direct evidence that links 8-OHdG with cancer risk is lacking, increased 8-OHdG has been found in different cancerous tissues (2). Moreover, urinary 8-OHdG was higher in small-cell lung carcinoma patients than in normal controls (3). A link between 8-OHdG formation and tobacco smoke carcinogenesis has been suggested by the fact that increased 8-OHdG levels were observed in lung DNA (4), peripheral leukocyte DNA (5), and the nuclei of oral mucosa (6) from smokers as compared with nonsmokers. In addition, a 50% increase in the levels of 8-OHdG was detected in the urine of smokers as compared with the urine of nonsmokers (7). Together, these data strongly implicate 8-OHdG formation in tobacco smoke-induced carcinogenic pathways.

Genetic susceptibility to environmental carcinogens, such as tobacco smoke, is thought to be attributable to genetic polymorphisms in metabolizing enzymes, which substantially alter the activation and elimination of carcinogens (8,9). Glutathione S-transferase (GST), a member of the phase II group of xenobiotic metabolizing enzymes, has been intensively studied at the levels of phenotype and genotype. Up to 50% of whites have no GSTM1 enzyme because of the homozygous deletion of the gene (10,11), referred to as the GSTM1 null genotype. The GSTM1 null genotype is found in 50% of Europeans, Japanese, and white Americans but in only one-quarter of Afro-Americans (12). Lack of M1 enzyme may result in deficient detoxification of tobacco smoke carcinogens leading to a slight increase in the risk of lung cancer (13,14). Similarly, genetic background has been demonstrated to be involved in the control of damaged DNA repair. The human OGG1 (hOGG1) gene encodes a DNA glycosylase/AP-lyase that is involved in the excision repair of 8-OHdG from oxidatively damaged DNA (15,16). Previous studies have revealed the presence of several polymorphisms at the hOGG1 locus. A C/G polymorphism at position 1245 in the 1-specific exon 7 of the hOGG1 gene results in an amino acid substitution from serine to cysteine in codon 326 (17). The hOGG1 protein encoded by the wild-type Ser³²⁶ allele exhibited substantially higher DNA repair activity than the Cys³²⁶ variant in an in vitro Escherichia coli complementation activity assay (17). Although no association between the Cys³²⁶ and Ser³²⁶ variants and breast cancer risk were observed in 2 recent breast cancer case-control studies (18,19), other studies have suggested that the Ser³²⁶Cys hOGG1 polymorphism may be associated with increased risk for lung (20) as well as esophageal (21) cancer. Significant increases in orolaryngeal cancer risk were observed for both the hOGG1 Ser³²⁶/Cys³²⁶ heterozygote and the hOGG1 Cys³²⁶/Cys³²⁶ homozygote (22).

Changes in dietary habits with the intake of more cancer-chemopreventive agents appear to be a practical approach for cancer prevention in subjects with increased oxidative stress, as is the case of smokers. People have been brewing tea made from the leaves of the Camellia sinensis plant for almost 50 centuries. Tea polyphenols scavenge active oxygen radicals (23) and inhibit DNA biosynthesis of the tumor cells (24) and chemocarcinogen-induced carcinogenesis (25). Tea can be easily consumed with one's ordinary meals, making compliance and adherence to dietary intervention more likely to succeed. Thus, the role of tea drinking as a potential inhibitor of carcinogenesis merits careful evaluation. We have previously shown that although there was no important interaction among smoking, hOGG1 genotypes, and green tea intake in terms of levels of urinary 8-OHdG (26), smokers with GSTM1 null genotypes were less likely to benefit from a green tea intervention (27).

We were interested in whether there were differences in increased oxidative stress susceptibility to smoking within the combined GSTM1 and hOGG1 genotypes and the impact of green tea drinking on this. Because both GSTM1 and OGG1 polymorphisms occur at reasonable frequencies, statistically meaningful conclusions can be drawn from studies of relatively small numbers of subjects.

	Materials and Methods

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
The detailed study protocol was published elsewhere (28). In summary, the study was a 3-arm randomized and controlled tea intervention trial among smokers. Each smoker was assigned randomly to drink 4 cups (960 mL)/d of decaffeinated green tea, decaffeinated black tea, or water. A total of 133 smokers completed the study. Thirty men and 90 women, with complete GSTM1 and hOGG1 genotype data were included in this analysis. The study was approved by the Institutional Review Board of the University of Arizona, and all of the subjects provided informed consent before enrollment.

Urinary 8-OHdG was measured by an ELISA kit, the validity and comparability of which to high-performance liquid chromatography with electrochemical detection had already been verified (29,30). First void urine samples were typically assayed in triplicate. The intra-assay coefficient of variation of this assay was 4.9%. Data were corrected by urinary creatinine concentration and expressed as nanograms 8-OHdG/mg creatinine.

Urinary creatinine levels were determined using a creatinine assay kit (31) with an intra-assay coefficient of variation of 3.6%. Total catechins in plasma were determined spectrophotometrically (32,33).

To assess individual GSTM1 genotypes (34) and the hOGG1 Ser³²⁶Cys polymorphism in exon 7 (35), DNA was extracted from whole blood and analyzed by polymerase chain reaction.

    Statistical methods. All statistical analyses were performed using Stata Statistical Software (Intercooled stata 7; StataCorp). Multiple linear regression models were used to estimate the main effects of green and black tea intake on creatinine-adjusted urinary 8-OHdG, with or without adjustment for potential confounders. Potential confounders considered were baseline levels of creatinine-adjusted urinary 8-OHdG, BMI, percentage body fat, amount of beverage consumed, cohort effect, physical activity, and antioxidants. Finally, we studied whether the effect of treatment varied by GSTM1 and hOGG1 status of the individual. Statistical tests were 2-sided with a significance level of 0.05.

	Results

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
The study population consisted of 30 male and 90 female smokers. The majority of the study participants (87%) were non-Hispanic whites, and the mean age of study participants was 57 y (range 18–79). Baseline characteristics were similar across the 3 intervention groups (Table 1). Adherence to the study protocol was high, with 95% of participants reporting consuming at least 4 cups (960 mL)/d of tea or water at each of the 4-mo study points. There were no differences in smoking level among the 3 groups and throughout the 4-mo intervention, and levels of creatinine-adjusted urinary cotinine did not change in any group during study participation.

The results of the final model for the 2 tea interventions, adjusted for baseline 8-OHdG levels, BMI, percentage body fat, amount of beverage consumed, cohort effect, and physical activity, showed a highly significant decrease in urinary 8-OHdG (–31%) after 4 mo of drinking decaffeinated green tea (P = 0.001). The change from baseline was significant in the GSTM1-positive green tea group (P = 0.006) but not in the GSTM1-negative green tea group (P = 0.07). We found no important interaction among smoking, hOGG1 genotypes, and tea intervention in terms of levels of urinary 8-OHdG (Table 2).

We then looked at smokers with combined GSTM1 and hOGG1 genotypes. Our data show that changes in urinary 8-OHdG from baseline were significant in GSTM1-positive green tea group smokers regardless of their hOGG1 genotype. No major effects were seen in smokers with the GSTM1 null genotypes regardless of their hOGG1 genotype.

	Discussion

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
Gene-environment interaction offers a possibility for defining individual genetic risk profiles, which would be important for identifying subgroups at highest risk for disease. Therefore, the probability that a smoker will develop lung cancer is related to both the dose of tobacco carcinogens and the individual's genetic background. Oxidative stress may be 1 mechanism by which tobacco smoke causes lung cancer, and the ratio of urinary 8-OHdG to urinary creatinine (8-OHdG/creatinine) is considered a good biological indicator of DNA oxidation (3). DNA damage is generally considered a necessary step in cancer initiation and is being used extensively in intervention studies [reviewed by Santella (36)]. GST constitutes the secondary defensive system against endogenous and/or exogenous oxidative stress.

Individuals lacking GSTM1 are thought to have impaired ability to eliminate carcinogens and therefore to be at increased cancer risk (37). The effect of this polymorphism was greater among heavy smokers (38). Although several epidemiological studies have found the null genotype to be associated with increased risk for the development of lung and other tobacco-related cancers (38–40), the findings in other studies are conflicting, and this association remains controversial (41–43). In our study, we used urinary 8-OHdG to determine the efficacy of regular tea drinking in decreasing the carcinogenic effects of cigarette smoking. We have previously reported a greater effect of green tea consumption on urinary 8-OHdG levels among GSTM1-positive than among GSTM1-negative subjects; that is, the change from baseline was significant in the GSTM1-positive green tea group but not in the GSTM1-negative green tea group (26).

There are several studies implicating oxidative stress and subsequent 8-OHdG formation in human lung carcinogenesis (3,44,45). The levels of 8-OHdG measured at any time represent the integration of a number of parameters, including reactive oxygen species production, cellular redox status, and antioxidant defense mechanisms, as well as DNA repair systems. Therefore, the interindividual differences in repairing these lesions may be associated with lung cancer susceptibility. Although several epidemiological studies have found the Cys/Cys genotype to be associated with increased risk for the development of lung and other tobacco-related cancers, these findings, especially in relation to the Ser/Cys genotype, are conflicting, and this association remains controversial (18–21,46,47). The Ser³²⁶Cys substitution polymorphism in the hOGG1 gene has been suggested, based on in vitro data, to reduce the activity of the enzyme. However, 8-OHdG levels in nuclear DNA were similar among lung cancer cells and leukocytes irrespective of the type of hOGG1 proteins expressed suggesting that 8-OHdG levels are maintained at a steady level, even though multiple hOGG1 proteins are produced as a result of genetic polymorphisms (17). In our study, the homozygous Cys/Cys genotype was present in only 10% of our study population. Therefore, the mutant types (Ser/Cys and Cys/Cys) were combined and compared with the Ser/Ser genotype. However, we should be aware that there is no solid biological rationale for the combination of Ser/Cys plus Cys/Cys as 1 group at this moment. We reported that smokers in the green tea group experienced a significant decrease in urinary 8-OHdG levels regardless of their hOGG1 genotypes (27).

Because of the complexity of cancer etiology, it is unlikely that a single polymorphism, either GSTM1 null or hOGG1 Cys/Cys plus Ser/Cys could explain most cancer susceptibility. The joint analysis of several metabolic gene polymorphisms implied in carcinogen activation, detoxification, and repair may provide new clues. Because the numbers of smokers in this study were reasonably large, the numbers in individual genotype classes were sufficient to examine the effects of combination of genotypes, for instance, to see the effects of green tea drinking on smokers who are both GSTM1 null and hOGG1 Cys/Cys plus Ser/Cys. Our data show that changes in urinary 8-OHdG from baseline were significant only in the GSTM1-positive green tea group smokers regardless of their hOGG1 genotype. Smoking behavior and levels of dietary and plasma antioxidants did not change in any group during study participation, indicating that changes in smoking behavior and/or diet are not responsible for the observed decrease in DNA damage.

In this randomized, controlled trial of smoking adults, daily drinking of 4 cups (960 mL) of decaffeinated green tea was associated with a significant decrease in urinary excretion of 8-OHdG among GSTM1-positive smokers regardless of their hOGG1 genotype. It is not known why decaffeinated green tea intervention resulted in a reduction in overall oxidative damage in GSTM1-positive smokers regardless of their hOGG1 genotype. Induction of phase II enzymes including GST has been postulated as 1 of the mechanisms responsible for the anticarcinogenic effect of green tea. Therefore, induction of GST enzyme activities may be more prominent in GSTM1-positive individuals. Moreover, Hardie et al. (48) reported that 8-OHdG levels in normal lung tissue DNA were not associated with constitutive hOGG1 genotype and that 8-OHdG levels in nuclear DNA were similar among lung cancer cells and leukocytes irrespective of the type of hOGG1 proteins expressed (17). This study shows that hOGG1 genotypes have no effect on the 8-OHdG levels in leukocytes and lung tissues, suggesting that the 8-OHdG levels are not dependent on the activity of this repair protein. This is consistent with our observations that green tea intervention effect on 8-OHdG levels is not modulated by hOGG1 genotypes.

Our data suggest that GSTM1 genotype may play a more important role in relation to DNA damage as compared with hOGG1 genotype. Further studies are necessary to understand the interaction among green tea consumption, GST genotypes, and hOGG1 genotypes in relation to smoking-induced oxidative DNA damage.

Some limitations of this present study should be noted. One potential limitation was that the study subjects were not unaware of the beverage they were consuming. It was necessary to use commercially available products because we were mainly interested in studying the effect of regular consumption of decaffeinated green and black tea in the forms in which they are commonly consumed. However, all the tea used in the trial was obtained from the same supplier, and tea content analyses were performed for each cohort to ensure standardization of product. Data from the self-reported diaries and recalls suggest high adherence with no use of other tea products to supplement the intervention. This high adherence to all regimens suggests that any bias based on prior beliefs of the intervention is reduced. There have been concerns raised about the validity of methods used to measure 8-OHdG (49). Nevertheless, even with the variation in methods, the creatinine-standardized concentrations of 8-OHdG seem broadly similar among different laboratories (50). Furthermore, the 4.9% intra-assay coefficient of variation we found in this study suggests satisfactory repeatability of the ELISA.

In conclusion, in this randomized controlled trial, drinking 4 cups (960 mL) of decaffeinated green tea daily for 4 mo was associated with statistically significant decrease in urinary 8-OHdG among GSTM1-positive heavy smokers regardless of their hOGG1 genotypes.

Other articles in this supplement include references (51–60).

	FOOTNOTES

 
¹ Published in a supplement to The Journal of Nutrition. Presented at the conference "Fourth International Scientific Symposium on Tea and Human Health," held in Washington, DC at the U.S. Department of Agriculture on September 18, 2007. The conference was organized by the Tea Council of the U.S.A. and was cosponsored by the American Cancer Society, the American College of Nutrition, the American Medical Women's Association, the American Society for Nutrition, and the Linus Pauling Institute. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Tea Council of the U.S.A. or the cosponsoring organizations. Supplement coordinators for the supplement publication were Lenore Arab, University of California, Los Angeles, CA and Jeffrey Blumberg, Tufts University, Boston, MA. Supplement coordinator disclosure: L. Arab and J. Blumberg received honorarium and travel support from the Tea Council of the U.S.A. for cochairing the Fourth International Scientific Symposium on Tea and Human Health and for editorial services provided for this supplement publication; they also serve as members of the Scientific Advisory Panel of the Tea Council of the U.S.A.

² Author disclosures: I. A. Hakim, H.-H. S. Chow, and R. B. Harris, no conflicts of interest.

³ This research was supported by a grant (ID 10005) from the Arizona Disease Control Research Commission. The decaffeinated tea used in the study was kindly supplied by Unilever Bestfoods North America, NJ, USA.

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58. Kelly SP, Gomez-Ramirez M, Montesi JL, Foxe JJ. L-Theanine and caffeine in combination affect human cognition as evidenced by oscillatory alpha-band activity and attention task performance. J Nutr. 2008;138:1572S–7S.[Abstract/Free Full Text]

59. Mandel SA, Amit T, Kalfon L, Reznichenko L, Youdim MBH. Targeting multiple neurodegenerative diseases etiologies with multimodal-acting green tea catechins. J Nutr. 2008;138:1578S–83S.[Abstract/Free Full Text]

60. Stote KS, Baer DJ. Tea consumption may improve biomarkers of insulin sensitivity and risk factors for diabetes. J Nutr. 2008;138:1584S–8S.[Abstract/Free Full Text]

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