sign in sign up
<<
Home , Myricetin

POLISH JOURNAL OF FOOD AND NUTRITION SCIENCES Pol. J. Food Nutr. Sci. 2003, Vol. 12/53, SI 1, pp. 141–146

THE COMT-MEDIATED METABOLISM OF AND AND ITS RELEVANCE TO CANCER RISK

Maria Kapiszewska*, Ma³gorzata Kalemba, Urszula Wojciech, Agnieszka Cierniak

Department of General Biochemistry, Faculty of Biotechnology, Jagiellonian University, Kraków, Poland

Key words: catechol-O-methyltransferase (COMT), , flavonoids, folate, oxidative DNA damage, misincorporation

Catechol-O-methyltransferase (COMT) is the Phase II able to efficiently catalyze detoxification of endo- and exogenous compounds containing catechol groups which otherwise may become toxic, mutagenic or even carcinogenic. Therefore, the enzyme activity itself and the fac- tors which influence the kinetics of such an inactivation are extensively studied. The COMT gene contains a single- polymorphism (SNP), which is associated with an amino acid shift val -> met. This gene is present in up to 75% of Caucasians. Such a mutation results in a significant decrease in enzyme activity. It was shown in several studies that individuals having the low activity allele (COMTL) face greater risk for developing breast cancer. The development of carcinogenesis may originate from catechol metabolites of estrogen which are not sufficiently O-methylated into inactive compounds because of low COMT activity. Beside this genetic determinant, an expression of the enzyme in a given individual or in a population is likely to be affected by environmental and lifestyle factors. Particularly, exogenous compounds which compete for enzyme activity, like dietary with catechol motif, the drug being a direct or indirect COMT inhibitor, or long-term exposure to exogenously administrated estrogen may contribute to carcinogenicity. COMT transfers a methyl group from S-adenyl-L-methionine to the catechol substrate. Therefore, the differences in metabolism of folate may also affect the individual response to catechol inactivation and then the cancer risk. Relationships between the level of endogenous DNA modifications involved in risk cancer and polymorphism in COMT gene, dietary habits, particularly high- diet as well as life style (estrogen level and drugs) are discussed in the paper.

INTRODUCTION the existence of inter-individual differences between metabolism of flavonoids due to the polymorphisms in Polyphenolic compounds are among the most discussed catechol-O-methyltranferase, the dietary status, particularly dietary ingredients. They are a class of phytochemicals the flavonoid and folate intake, and the exposure to found in high concentrations in wine, tea, and a wide estrogen. This hypothesis is confronted below with the variety of other plants and are associated with prevention of results of our pilot studies. heart disease and cancer [Hertog, 1996; Hanninen, et al., 1999; Hollman & Katan, 1999a; Riemersma et al., 2001; FLAVONOID INTAKE AND ITS BIOACTIVE ROLE Silalahi, 2002, Mojzisova & Kuchta, 2001]. One of the most nutritionally important are flavonoids and The average, daily, mixed flavonoids, human intake is isoflavones, commonly called “” [Potter estimated to be in the range of 20 to 1000 mg [Hertoget al., & Steinmetz, 1996; Reinli & Block, 1996]. Their 1993; Hollman & Katan, 1997, 1998, 1999b; Scalbert and estrogenic effect has led researchers to regard these & Williamson, 2000; Aherne & O'Brien, 2002; Pierpoint, compounds as potential anticarcinogens [Adlercreutz et al., 1986]. These compounds are present in fruits, vegetables, 1992; Zava & Duwe, 1997; Griffiths et al., 1998]. grains, nuts, tea, and wine [Hertog et al., 1992]. It was shown While reviewing the literature of the subject it became that after a -free diet followed by a single meal clear that although high fruit and vegetable intake has been containing 200 mg of quercetin, human plasma levels linked with a reduced risk of cancer, epidemiological data reached >1 µM of quercetin alone as soon as 1.5-2 h after do not confirm that observation [Waladkhani & Clemens, ingestion. Moreover, the half-life of quercetin was 25 h, 1998]. Several studies reported inverse relationship implying that repeated dietary intake of quercetin can lead between intake of vegetables and fruits and cancer to much higher blood concentrations [Hollman, 1997; [Eastwood, 1999; Shih et al., 2000; Birt et al., 2001; Silalahi, Hollman & Katan, 1997, 1998, 1999a; Hollman et al., 1997a, 2002], while a non-significant inverse association of fruit, b]. Thus, the biological effects of this compound should be vegetable and flavonoid intake and cancer were announced studied within this concentration range for nutritional by others [Arts et al., 2001; Hertog, 1996]. What is the relevance. Our results showed that quercetin at the reason for such an inconsistence? One possible answer is concentration as low as 1 µM has the protective effect on

*Author's address for correspondence: Maria Kapiszewska, Department of General Biochemistry, Faculty of Biotechnology, Jagiellonian University, ul. Gronostajowa 7; 30-388 Kraków, Poland; tel. (48 12) 252 61 39; fax: (48 12) 262 21 74; e-mail: [email protected] 142 M. Kapiszewska et al. the oxidative DNA damage induced by in calculated using published values for content (USDA human lymphocytes (Figure 1). This confirms earlier findings database for the flavonoids content of selected food in [Aherne & O'Brien, 1999; Anderson et al., 2000; Collins vegetables, fruits, beverages, herbs, spices, tea, coffee, & Dusinska, 2002] that some flavonoids are among the most chocolate etc.). According to our results (Figure 2) the potent anti-oxidants and because of that might protect against main dietary sources of flavonoids are not fruit and cancer through inhibition of oxidative damage, which is likely vegetables but tea, coffee, chocolate, wine and beer. to be an important cause of mutation. Other proposed These results confirm data published by Scalbert and mechanisms include antiproliferation, estrogenic/anti- Williamson [2000]. -estrogenic activity, induction of cell-cycle arrest and , modulation of activities of many , EFFECT OF FLAVONOIDS AND induction of detoxification enzymes, and changes in cellular ON OXIDATIVE DNA DAMAGE signaling [Aherne & O'Brien, 1999, 2000; Anderson et al., 1997, 1998, 2000, 2001; Kong et al., 2001; Myhrstad et al., 2002; The oxidative DNA damage is induced by oxygen Sato et al., 2002; Walle & Walle, 2002]. radicals and other reactive species which are normally formed during cellular metabolic processes and are also 25 raised by metabolism of environmentally available 20 xenobiotics, subsequently inhibiting DNA replication and transcription [Stohs, 1995; Williams & Jeffrey, 2000; 15 Fujikawa & Kasai 2001; Owuor & Kong, 2002]. 10 The oxidatively damaged DNA can play a significant role in

5 mutagenesis, cancer, aging, and other human pathologies. The level of oxidative DNA damage depends on the level 0

OTM (oxidative DNA damage parameter) 2 2 2 and activities of anti-oxidative enzymes and can be O 2 O 2 O O O 2 1Q 2 2 2 2 H 10 Q 20 Q 40 Q control decreased by supplementation with pure or 1Q+H 10 Q +H 20 Q + H 40 Q + H with food rich in antioxidants, namely vitamins C, A, E and Quercetin [µM] beta carotenoids [Krishnaswamy & Raghuramulu, 1998; FIGURE 1. Effect of different doses of quercetin on oxidative DNA Collins et al., 2003]. Furthermore, the antioxidant ability of damage induced by hydrogen peroxide treatment. Lymphocytes were flavonoids and other micronutrients may also account for incubated with different concentration of quercetin for 1 h and next cells the beneficial effects of fruits and vegetables in human were exposed for 5 min to 25 µM hydrogen peroxide at 4°C. The oxida- health. Among the numerous oxidized DNA bases, most tive DNA damage was assesed by Comet assay, modified by using the often occurs the 8-oxo-dG, 8-oxo-7,8-dihydro- endonuclease III which recognized apurinic sites and oxidized pirimidine. -2'deoxyguanosine (8-oxo-dG) and 2,4-diamino-5 formami- dopyrimidine (Fapy-G). The elevated levels of 8-oxo-dG To estimate the amount of flavonoid intake among have been reported in tumor tissue; this can suggest that Polish young women, nineteen subjects recorded their accumulation of oxidative DNA damage can play food, beverages, herbs and spices consumption for two a significant role in carcinogenesis. Moreover, an enhanced weekdays and one weekend throughout a three-week level of such lesions may be used as a predictive assay of the period in a winter month (9 records). As all individual risk cancer and as biomarkers [Cadet et al., 1997]. Oxidative questionnaires were computerized, the amount of dietary DNA damage occurs due to of catechol compounds was estimated according to a specifically estrogens and can be fixed as mutation due to proliferating developed program, linked to recently updated Polish food activity of result in enhancement of the risk of database. The intake of four subclasses of flavonoids cancer. Oxidized DNA bases can be directly measured by containing catechol groups: , flavonons, flava- the high-performance liquid chromatography (HPLC). nones and flavan-3-ols, as well as anthocyanidines, was An alternative approach to the measurement of oxidized bases makes the use of repair endonucleases with the

120 appropriate lesion specificities-endonuclease III, for oxidized and formamidopyrimidine glycosylase 100 (Fapy-G for 8-OHgua) for oxidized pyrines [Cadet et al., % of flavonoids from 80 fruits and vegetables 2000; Lunec et al., 2002]. These enzymes introduce breaks

60 at sites of damage in DNA, which creates the condition for % of flavonoids from their detection by the comet assay (single cell gel % of flavonoids 40 other sources than fruits and vegetables electrophoresis) [Duthie & Hawdon, 1998; Angelis et al., 20 1999, 2000; Collins & Dusinska, 2002]. This modified comet assay, like other enzyme-linked DNA breakage assays, gives 0 1 4 7 10 13 16 19 value for endogenous oxidative base damage that is more Subject than 10-fold lower than most estimated from HPLC. The method, which measures DNA strand breaks at the level FIGURE 2. The percentage of the total daily flavonoid intake from different sources of common food for individual subject is calculated of single cells, is very easily applied to human lymphocytes, by using USDA database (for the flavonols, flavonons, flavanones, and therefore lends itself to human biomonitoring studies. flavan-3-ols and anthocyanidines content of selected food in Not only flavonoids but also some nutrients affect the vegetables, fruits, beverages, herbs, spices, tea, coffee, chocolate etc. production, metabolism and bioavailability of hor- based on collected dietary diary). mones [Xu et al., 1999]. It means that the level of estrogens COMT and flavonoids and estrogen 143

TABLE 1. The statistically significant correlation between the oxidative DNA lesion and uracil misincorporation into DNA (assessed by Comet assay single cell gel electrophoresis, respectively with endonuclease III or uracil DNA glycosylase) and flavonoid intake, serum folate concentra- tion and COMT polymorphism, before or after 400 µg/day folic acid supplementation for four weeks.

DNA damage (comet assay parameter) Σ Flavonoids Folate in serum COMT*H

Endogenous oxidative DNA damage positive no positive (after folate (before folate supplementation) supplementation)

Uracil misincorporation into DNA negative negative negative (before folate (after folate (after folate supplementation) supplementation) supplementation) during the menstrual cycle phase or pregnancy must be vegetables and fruits and oxidative damage was found in considered while studying the influence of nutritional peripheral lymphocytes in a Mediterranean population status on the endogenous DNA damage. Results of [Giovannelli et al., 2002]. population-based and of in vitro and in vivo studies suggest that estrogens, under certain conditions, may be INFLUENCE OF THE HOST FACTORS (A GENETIC carcinogenic [Sasco, 2001]. POLYMORPHISM – COMT GENE, FOLATE, FLAVO- The mechanism of estrogens contribution to the NOIDS, B12, B6 INTAKE, AND ESTRADIOL LEVEL) ON development of human cancer is still unknown. However, BIOACTIVITY OF DIETARY FLAVONOIDS two possible hypotheses are subsequently advanced. The estrogen-induced tumor development is mediated by The circulating levels of unmetabolized dietary the estrogen--based proliferation of cells, phytochemicals, particularly quercetin, depend on the accompanied by increased probability of mutation and the activity of catechol-O-methyltransferase (EC 2.1.1.6), an induction of DNA damage by the , enzyme which rapidly converts quercetin to the 3'-O- such as superoxide [Lord et al., 2002]. Moreover, the -methylquercetin, a non-bioactive form. The rate of the catechol estrogens may give rise to reactive quinones COMT-catalyzed methylation depends on several factors, capable of forming adducts to DNA and enhance the such as COMT genotype, concentration of catechol single/double DNA strand breaks as well as oxidative estrogen, folates, S-adenosyladenine (SAM, vitamin B12 and modification of nitrogen and pirimidine bases B6) [Goodman et al., 2001a, b]. The catechol-O- [Li & Li, 1987; Zhu & Liehr, 1994]. That reaction can be -methyltransferase catalyses the transfer of the methyl blocked via several detoxication pathways, including group to catecholamines and catechol estrogens. Inhibition O-methylation of catechol estrogens by catechol-O-methyl of the COMT-mediated O-methylation of endogenous transferase (COMT). COMT is polymorphic in human 2- and 4-hydroxylated estrogens by phytochemicals may population, which results in differences in enzyme activity lead to elevated tissue levels of pro-carcinogenic 4-hydroxy- and causes different detoxication of catechol estrogens estradiol and to a decreased tissue level of the anti- [Millikan et al., 1998; Lavigne et al., 2001]. The increase of carcinogenic 2-MeO-E2 [Lavigne et al., 2001]. It was shown, cancer risk was also observed after hormonal replacement that chronic administration of dietary quercetin enhances therapy [Sitruk-Ware, 2002]. It means that the factors which the E2-induced kidney tumor formation in male Syrian affect the COMT activity can modify the risk of hormone- hamsters [Zhu & Liehr, 1996]. -dependent cancers due to the accumulation of potentially COMT exists in most tissues of human body. Its activity carcinogenic metabolites of estradiol. in some peripheral tissues was shown to have age- and sex- Our studies did not show any statistically significant -related differences [Mannisto, 1999] The distribution of correlation between phases of menstrual cycle, defined as COMT activity in Caucasian individuals was polymorphic follicular (9-17 days) or non-follicular, and the oxidative with the trimodal distribution, with 25% of the subjects DNA damage. The amount of oxidized DNA, incised by homozygous (COMTLL) for the low activity thermo-labile endonuclease III digestion, was evaluated using the alkaline COMT; 25% of the subjects homozygous (COMT HH) for comet assay in blood samples taken during collection of the high-activity thermostable enzyme; and 50% of the nutritional data. In turn, the positive correlation was found subjects heterozygous (COMTLH) [Ishiguro et al., 1999; between the oxidative DNA damage/modification and Goodman et al., 2001a, b]. The significantly lower COMT flavonoids intake (Table 1) but only after four weeks of activity may suggest that under chronic estrogen treatment folate supplementation (400 µg/day). It was reported, that at high doses, and with the excess intake of dietary the amount of oxidative DNA damage and DNA adduct flavonoids, the concentration of quercetin may exceed the in human lymphocytes was higher during the summer capacity of COMT to effectively catalyze their season [Giovannelli et al., 2002, Li & Li, 1987; Milikan et O-methylation into inactive metabolites. The resulting al., 1998; Mojzisova & Kuchta, 2001]. The impact of accumulation of catechol estrogens and quercetin may coffee consumption on the lymphocyte DNA oxidation is contribute to the carcinogenicity in such individuals not consistent: in one case - a positive correlation was [Zhu et al., 1994; Zhu & Liehr, 1994]. Some studies found [Giovannelli et al., 2002], in another - a negative suggested that COMTL allele was more frequently seen in one [van Zeeland et al., 1999]. Similarly to our findings, patients with breast cancer than in healthy controls the positive tendency between the total consumption of [Lavigne et al., 1997, 2001; Huang et al., 1999] 144 M. Kapiszewska et al.

The postmenopausal women with the COMTLL genotype, REFERENCES which used estrogens for longer than 30 months, and women with the COMTL allele-containing genotypes which 1. Adlercreutz H., Mousavi Y., et al., Dietary phytoe- had menarche at <12 years of age had the significantly strogens and cancer: in vitro and in vivo studies. increased risk of cancer. Moreover, a recent study showed J. Steroid. Biochem. Mol. Biol., 1992, 41, 3–8, that the presence of the increased number of COMTL allele 331–337. was significantly associated with higher breast cancer risk in 2. Aherne S.A., O'Brien N.M., Protection by the flavonoids women with the below median level of folate intake or the myricetin, quercetin, and against hydrogen pero- above median level of homocyteine. Both folate and xide-induced DNA damage in Caco-2 and Hep G2 cells. homocyteine can indirectly affect the COMT-mediated Nutr. Cancer, 1999, 34, 2, 160–166. O-methylation of catechol estrogens through modulating 3. Aherne S.A., O'Brien N.M., Mechanism of protection by levels of S-adenosylhomocyteine (SAH), a strong non- the flavonoids, quercetin and rutin, against tert-butylhy- -competitive inhibitor of COMT. It was shown that folate droperoxide- and menadione-induced DNA single deficiency significantly increases strand breakage and uracil strand breaks in Caco-2 cells. Free Radic. Biol. Med., misincorporation in cell [Duthie et al., 2000]. These results 2000, 29, 6, 507–514. demonstrate that folic acid modulates DNA repair, DNA 4. Aherne S.A., O'Brien N.M., Dietary flavonols: strand breakage, and uracil misincorporation in immorta- chemistry, food content, and metabolism. Nutrition, lized human colonocytes, and that folate deficiency 2002, 18, 1, 75–81. substantially decreases DNA stability in cell. 5. Anderson D., Basaran N., Dobrzynska M.M., Basaran Our studies indicate that COMT *H polymorphism A.A., Yu T.W., Modulating effects of flavonoids on food (higher enzyme activity) is positively correlated with the mutagens in human blood and sperm samples in the amount of oxidative DNA damage and negatively comet assay. Teratog Carcinog. Mutagen., 1997, correlated with uracil misincorporation into DNA. 17, 2, 45–58. Moreover, the uracil misincorporation into DNA is much 6. Anderson D., Dobrzynska M.M., Basaran N., Basaran lower after folate supplementation (Table 1), indicating A., Yu T.W., Flavonoids modulate comet assay respon- that both COMT activity and folate level can influ- ses to food mutagens in human lymphocytes and sperm. ence genetic stability defined as amount of DNA Mutat Res., 1998, 402, 1–2, 269–277. damage/modification. 7. Anderson R.F., Amarasinghe C., Fisher L.J., Mak W.B., Packer J.E., Reduction in free--induced DNA SUMMARY strand breaks and base damage through fast chemical repair by flavonoids. Free Radic. Res., 2000, This paper reviews most recent studies analyzing the 33, 1, 91–103. association between consumption of fruits and vegetables, 8. Anderson R.F., Fisher L.J., Harris T., The 'pivotal their flavonoid content and cancer risk. Reasons for the antioxidant' hypothesis for the role of flavonoids in their inconclusiveness of the epidemiological data on this reduction of HO* radical-induced damage on DNA. matter are discussed in the light of factors, such as genetic Redox Rep., 2001, 6, 3, 197–199. polymorphism of the catechol-O-methyltransferase 9. Angelis K.J., Dusinska M., Collins A.R., Single cell gel (COMT), an enzyme responsible for the inactivation of electrophoresis: detection of DNA damage at different flavonoid and catechol estrogen, and the dietary status, levels of sensitivity. Electrophoresis, 1999, 20, particularly folic acid and flavonoid intake. The results of 10, 2133–2138. reviewed studies, as well as our own preliminary research, 10. Angelis K.J., McGuffie M., Menke M., Schubert I., showed that health benefits of flavonoids, defined as Adaptation to alkylation damage in DNA measured by a correlation between their intake and the amount of the comet assay. Environ. Mol. Mutagen., 2000, endogenous DNA damage/modification, depend on 36, 2, 146–150. inherited variation amongst individuals in their 11. Arts I.C., Hollman P.C., Bueno De Mesquita H.B., genetically defined ability to metabolize flavonoids. Feskens E.J., Kromhout D., Dietary catechins and In addition, our research suggests the importance of epithelial cancer incidence: the Zutphen elderly study. folate, as a methyl group supplier, in maintaining genetic Int. J. Cancer, 2000, 92, 2, 298–302. stability (as reflected by a decreased amount of uracil 12. Birt D.F., Hendrich S., Wang W., Dietary agents in cancer misincorporation into DNA). These findings were prevention: flavonoids and isoflavonoids. Pharmacol. discussed in relation to COMT polymorphism. It was Ther., 2001, 90, 2–3, 157–177. concluded that the bioactivity of flavonoids and therefore 13. Cadet J., Berger M., Douki T., Ravanat J.L., Oxidative their beneficial effect on health can be related to damage to DNA: formation, measurement, and biologi- variation in polymorphic form of COMT, to dietary status cal significance. Rev. Physiol. Biochem. Pharmacol., and lifestyle (estrogen lifetime exposure). 1997, 131, 1–87. 14. Cadet J., Bourdat A.G., D'Ham C., Duarte V., ACKNOWLEDGEMENT Gasparutto D., Romieu A., Ravanat J.L., Oxidative base damage to DNA: specificity of base excision repair The research was carried out as part of the research enzymes. Mutat Res., 2000, 462, 2–3, 121–128. project No. 3 P05E 016 25 funded by the State Committee 15. Collins A.R., Dusinska M., Oxidation of cellular DNA for Scientific Research. measured with the comet assay. Methods Mol. Biol., 2002, 186, 147–159. COMT and flavonoids and estrogen 145

16. Collins A.R., Harrington V., Drew J., Melvin R.V., 33. Hollman P.C., Katan M.B., Health effects and bioavail- Nutritional modulation of DNA repair in a human inter- ability of dietary flavonols. Free Radic. Res., 1999, 31 vention study. Carcinogenesis, 2003, 24, 3, 511–515. Suppl, S75–80. 17. Duthie S.J., Hawdon A., DNA instability (strand break- 34. Hollman P.C., Tijburg L.B., Yang C., Bioavailability of age, uracil misincorporation, and defective repair is flavonoids from tea. Crit. Rev. Food Sci. Nutr., 1997, 37, increased by folic acid depletion in human lymphocytes 8, 719–738. in vitro. Faseb J., 1998, 12, 14, 1491–1497. 35. Hollman P.C., van Trijp J.M., Mengelers M.J.,de Vries 18. Duthie S.J , Narayanan S., Blum S., Pirie L., Brand J.H., Katan M.B., Relative bioavailability of the antioxi- G.M., Folate deficiency in vitro induces uracil misincor- dant flavonoid quercetin from various foods in man. poration and DNA hypomethylation and inhibits DNA FEBS Lett., 1997a, 418, 1–2, 152–156. excision repair in immortalized normal human colon 36. Huang C.S., Chern H.D., Breast cancer risk associated epithelial cells. Nutr. Cancer, 2000, 37, 2, 245–251. with genotype polymorphism of the estrogen-metaboliz- 19. Eastwood M.A., Interaction of dietary antioxidants in ing genes CYP17, CYP1A1, and COMT: a multigenic vivo: how fruit and vegetables prevent disease? study on cancer susceptibility. Cancer Res., 1999, 59, Qjm, 1999, 92, 9, 527–30. 19, 4870–4875. 20. Fujikawa K., Kasai H., Oxidative DNA damage, 37. Ishiguro H.T., Haruo Shibuya T., Toru M., Saito Arinami Tanpakushitsu Kakusan Koso, 2001, 46, 8 Suppl., T., Association study between high and low activity poly- 1139–1145. morphism of catechol-O-methyltransferase gene and 21. Giovanneli L., Saieva C., Masala G., Testa G., Salvini S., . Psychiatr. Genet., 1999, 9, 3, 135–138. Pitozzi V., Riboli E., Dolara P., Palli D., Nutritional and 38. Kong A.N., Owuor E., Yu R., Hebbar V., Chen C., Hu lifestyle detreminants of DNA oxidative damage: a study R., Mandlekar S., Induction of xenobiotic enzymes by in a Mediterranean population. Carcinogenesis, 2002, the MAP kinase pathway and the antioxidant or elec- 23, 9, 1483–1489. trophile response element (ARE/EpRE). Drug Metab. 22. Goodman J.E., Wu K., Helzlsouer K.J., Strickland P.T., Rev., 2001, 33, 3–4, 255–271. Selhub J., Yager J.D., Lavigne J.A., COMT genotype, 39. Krishnaswamy K., Raghuramulu N., Bioactive phyto- micronutrients in the folate metabolic pathway and chemicals with emphasis on dietary practices. Indian J. breast cancer risk. Carcinogenesis, 2001, 22, Med. Res., 1998, 108, 167–181. 10, 1661–1665. 40. Lavigne J.A., Goodman J.E., Fonong T., Odwin S., 23. Goodman M.T., Kolonel L.N., Terada K., Donlon T.A., He P., Roberts D.W., Yager J.D., The effects of cate- Wilkens L.R., Guo C., Le Marchand, McDuffie L.K., chol-O-methyltransferase inhibition on estrogen Case-control study of ovarian cancer and polymor- metabolite and oxidative DNA damage levels in estra- phisms in genes involved in catecholestrogen formation diol-treated MCF-7 cells. Cancer Res., 2001, 61, and metabolism. Cancer Epidemiol. Biomarkers Prev., 20, 7488–7494. 2001, 10, 3, 209–216. 41. Lavigne J.A., Helzlsouer K.J., Huang H.Y., Strickland 24. Griffiths K., Denis L., Turkes A., Morton M.S., P.T., Bell D.A., Selmin O., Watson M.A., Hoffman S., Phytoestrogens and diseases of the prostate gland. Comstock G.W., Yager J.D., An association between the Baillieres Clin. Endocrinol. Metab., 1998, 12, 4, 625–647. allele coding for a low activity variant of catechol-O- 25. Hanninen O., Rauma A.L., Kaartinen K. Nenonen M., -methyltransferase and the risk for breast cancer. Vegan diet in physiological health promotion. Acta Cancer Res., 1997, 57, 24, 5493–5497. Physiol. Hung., 1999, 86, 3–4, 171–180. 42. Li J.J., Li S.A., Estrogen carcinogenesis in Syrian ham- 26. Hertog M.G., Epidemiological evidence on potential ster tissues: role of metabolism. Fed Proc., 1987, 46, health properties of flavonoids. Proc. Nutr. Soc., 1996, 5, 1858–63. 55, 1B, 385–397. 43. Lord R.S., Bongiovanni B., Bralley J.A., Estrogen 27. Hertog M.G., Hollman P.C., Katan M.B., Kromhout D., metabolism and the diet-cancer connection: rationale Intake of potentially anticarcinogenic flavonoids and for assessing the ratio of urinary hydroxylated estrogen their determinants in adults in The Netherlands. Nutr. metabolites. Altern. Med. Rev., 2002, 7, 2, 112–129. Cancer, 1993, 20, 1, 21–29. 44. Lunec J., Holloway K.A., Urinary 8-oxo-2'-deoxyguano- 28. Hertog M.G.L., Hollman P.C.H., Content of potentially sine: redox regulation of DNA repair in vivo? Free anticancerogenic flavonoids of 28 vegetables and 9 fruits Radic. Biol. Med., 2002, 33, 7, 875–885. commonly consumed in the Netherlands. J. Agric. Food 45. Mannisto P.T., Kaakkola S., Catechol-O-methyltransferase Chem., 1992, 40, 2379–2383. (COMT): biochemistry, molecular biology, pharmacology, 29. Hollman P.C., Bioavailability of flavonoids. Eur. J. Clin. and clinical efficacy of the new selective COMT inhibitors. Nutr., 1997, 51 Suppl. 1, S66–69. Pharmacol Rev., 1999, 51, 4, 593–628. 30. Hollman P.C., Katan M.B., Absorption, metabolism and 46. Millikan R.C., Pittman G.S., Tse C.K., Duell E., health effects of dietary flavonoids in man. Biomed. Newman B., Savitz D., Moorman P.G., Boissy R.J., Bell Pharmacother., 1997, 51, 8, 305–310. D.A., Catechol-O-methyltransferase and breast cancer 31. Hollman P.C., Katan M.B., Bioavailability and health risk. Carcinogenesis, 1998, 19, 11, 1943–1947. effects of dietary flavonols in man. Arch. Toxicol., 1998, 47. Mojzisova G., Kuchta M., Dietary flavonoids and risk of Suppl 20, 237–248. coronary heart disease. Physiol. Res., 2001, 50, 6, 529–535. 32. Hollman P.C., Katan M.B., Dietary flavonoids: intake, 48. Myhrstad M.C., Carlsen H., Nordstrom O., Blomhoff health effects and bioavailability. Food Chem. Toxicol., R., Moskaug J.J., Flavonoids increase the intracellular 1999, 37, 9–10, 937–942. level by transactivation of the gamma-glu- 146 M. Kapiszewska et al.

tamylcysteine synthetase catalytical subunit promoter. 60. Stohs S.J., The role of free radicals in toxicity and dis- Free Radic. Biol. Med., 2002, 32, 5, 386–393. ease. J. Basic Clin. Physiol. Pharmacol., 1995, 6, 3–4, 49. Owuor E.D., Kong A.N., Antioxidants and oxidants reg- 205–228. ulated signal transduction pathways. Biochem. 61. van Zeeland AA., de Groot A.J., Hall J., Donato F., 8- Pharmacol., 2002, 64, 5–6, 765–70. Hydroxydeoxyguanosine in DNA from leukocytes of 50. Pierpoint W.S., Flavonoids in the human diet. Prog. Clin. healthy adults: realtionship with cigarette smoking, Biol. Res., 1986, 213, 125–140. environmental tabacco smoke, and coffee con- 51. Potter J.D., Steinmetz K., Vegetables, fruit and phytoe- sumption, Mut. Res., 1999, 439, 249–257. strogens as preventive agents. IARC Sci. Publ., 62. Waladkhani A.R., Clemens M.R., Effect of dietary phy- 1996, 139, 61–90. tochemicals on cancer development (review). Int. J. 52. Reinli K., Block G., content of foods Mol. Med., 1998, 1, 4, 747–753. - a compendium of literature values. Nutr. Cancer, 1996, 63. Walle U.K., Walle T., Induction of human UDP-glu- 26, 2, 123–148. curonosyltransferase UGT1A1 by flavonoids - struc- 53. Riemersma R.A., Rice-Evans C.A., Tyrrell R.M., tural requirements. Drug Metab. Dispos., 2002, 30, Clifford M.N., Lean M.E., Tea flavonoids and cardio- 5, 564–569. vascular health. Qjm., 2001, 94, 5, 277–282. 64. Williams G.M., Jeffrey A.M., Oxidative DNA damage: 54. Sasco A.J., Epidemiology of breast cancer: an environ- endogenous and chemically induced. Regul. Toxicol. mental disease? Apmis, 2001, 109, 5, 321–332. Pharmacol., 2000, 32, 3, 283–292. 55. Sato T., Koike L., Miyata Y., Hirata M., Mimaki Y., 65. Xu X., Duncan A.M., Merz-Demlow B.E., Phipps W.R., Sashida Y., Yano M., Ito A., Inhibition of activator pro- Kurzer M.S., Menstrual cycle effects on urinary estrogen tein-1 binding activity and phosphatidylinositol 3-kinase metabolites. J. Clin. Endocrinol. Metab., 1999, 84, 11, pathway by nobiletin, a polymethoxy flavonoid, results 3914–3918. in augmentation of tissue inhibitor of metalloproteina- 66. Zava D.T., Duwe G., Estrogenic and antiproliferative ses-1 production and suppression of production of properties of and other flavonoids in human matrix metalloproteinases-1 and -9 in human fibrosarco- breast cancer cells in vitro. Nutr. Cancer, 1997, ma HT-1080 cells. Cancer Res., 2002, 62, 4, 1025–1029. 27, 1, 31–40. 56. Scalbert A., Williamson G., Dietary intake and bioavail- 67. Zhu B.T., Bui Q.D., Weisz J., Liehr J.G., Conversion of ability of polyphenols. J. Nutr., 2000, 130, 8S Suppl, to 2- and 4-hydroxyestrone by hamster kidney 2073S–2085S. and liver microsomes: implications for the mechanism of 57. Shih H., Pickwell G.V., Differential effects of flavonoid estrogen-induced carcinogenesis. Endocrinology, 1994, compounds on tumor promoter-induced activation of 135, 5, 1772–1779. the human CYP1A2 enhancer. Arch. Biochem. 68. Zhu B T., Liehr J.G., Quercetin increases the severity of Biophys., 2000, 373, 1, 287–294. estradiol-induced tumorigenesis in hamster kidney. 58. Silalahi J., Anticancer and health protective properties Toxicol. Appl. Pharmacol., 1994, 125, 1, 149–158. of citrus fruit components. Asia Pac. J. Clin. Nutr., 2002, 69. Zh, B.T., Liehr J.G., Inhibition of catechol O-methyl- 11, 1, 79–84. transferase-catalyzed O-methylation of 2- and 4-hydro- 59. Sitruk-Ware R., Progestogens in hormonal replacement -xyestradiol by quercetin. Possible role in estradiol- therapy: new molecules, risks, and benefits. Menopause, -induced tumorigenesis. J. Biol. Chem., 1996, 271, 2002, 9, 1, 6–15. 3, 1357–1363.