Tea and Cancer Prevention

Mutations of the cellular DNA are a key step leading to cancer (5). Mutational events can be used as markers for environmental genotoxic products that might be possible cancer risks (32). This approach is effective in research on products that might have antimutagenic and, thus, likely anticarcinogenic effects.

This method has been applied to study the effect of tea polyphenols from black tea and from green tea. It was found that both types of polyphenols decreased in a dose-related fashion the mutagenicity of different types of carcinogens (Table 3). In another series of bioassays, similar results were obtained, demonstrating the stability and reliability of these rapid tests in forecasting the chemopreventive potential of inhibitors such as tea extracts (Table 4) (33-35). Selenium potentiated the effect of green tea on the mutagenicity of 2-amino-3-methylimidazo-[4,5-f ]quinoline (36). Parallel to the effects on DNA-reactive carcinogens, tea inhibited the formation of cancer of the colon and the mammary gland in rats (37-39). Even a low dose of tea was effective (Table 5) (37).

Cancer of the esophagus is decreased in animal models by tea (40), just as a lower risk is noted in parts of China of cancer of the esophagus in people who drink tea (41,42, reviewed also in Refs. 43,44). Similar results hold for oral cancer (45). There are more cigarette smokers in Japan than in the United States but the incidence of lung cancer in Japan is lower than in the United States, possibly because there are more tea drinkers in Japan, accounting for this protection. In parallel, mice and rats exposed to the tobacco-specific nitrosamines displayed a lower incidence of lung tumors when the animals were drinking tea (46). Even ''spontaneous" lung tumors in mice were decreased by intake of black or green tea (47). The mechanism may depend on a reduction of oxidative stress (48). This inhibition by tea was due to lower

TABLE 3 Effect of Tea-Derived Polyphenols on Mutagenicity of Genotoxic Carcinogens

Polyphenol, type and amount (mg)

S.t.a Mutagenicity 60 100 B

2-Acetylaminofluorene

2-Aminoanthracene

2-Amino-3-methylimidazo-

[4,5-f]-quinoline 2-amino-1-methyl-6-phyenlimidazo[4,5-b]-pyridine Benzidine Aflatoxin B, Benzo[a] pyrene 1,2-Dibromoethane 2-Nitropropane 1 -Nitropyrene 2-Chloro-4-methylthio-

butanoic acid9 A/-Nitrosodimethylamineh 4-(/V-Nitrosomethylamino)-1 -[3-pyridyl]-1 -butanoneh aS.t.: Salmonella typhimurium strain for a given carcinogen; an S9 fraction from rat liver induced with ^-naphthoflavone and phenobarbital was used in all tests, except as shown. The spontaneous revertants rate for S. typhimuriumT A98 + S9 was 34 in DM SO (100 ^L) or 32 in aqueous buffer; for TA 100 + S9the rate was 134 in DMSO,and 124 in buffer. In all tests reported, the net values are shown, i.e., the gross data minus the appropriate background value, obtained in simultaneous determinations. Likewise, the three polyphenones(propriatory name of polyphenols) used gave background readings atthe 3 dose levels used. Thus, in S. typhimurium TA98 + S9, polyphenon 60 gave gross readings of 30,30, and 32 rev/plate at 1, 2, and 3 mg/plate, respectively. The corresponding values for polyphenon 100 were 45,39, and 36andforpolyphenon B33,32, and 31. InS. typhimurium TA100 + S9, the values for 1,3, and 3 mg polyphenon 60 were 114,132, and 114, for polyphenon 100,130,114, and 108, and for polyphenon B, 124,104, and 104. The bacterial lawn displayed no evidence of toxicity in the tests with the polyphenols alone, or in the inhibition assays involving each carcinogen and the three dose levels of the polyphenols.

"Polyphenols 60 and 100, from green tea, and polyphenol B, from blacktea, were kind gifts from Dr. Y. Hara, Tokyo. Water solutions of the polyphenols were made by dissolving 1 g of a polyphenol in 20ml_H20,and using 20 ^L (1 mg), 40 \xl (2 mg), and 60 \iL (3 mg).

cRevertants/plate, mean ± standard error; all tests were done in triplicate.

dAII values were significantly different (p < 0.05) with added polyphenols, except where specifically shown. eNot statistically different from mutagenicity without polyphenol. 'Significant (p < 0.05) increase over mutagenicity without polyphenol. 9Direct-acting mutagen; active without S9 fraction.

hThe nitrosamines displayed no significant mutagenicity with an S9 fraction from induced rat liver; utilizing hamster liver S9 fraction at a fourfold level of protein nitrogen worked reliably in these inhibition experiments. Source: Ref. 33.

50

98

1196

+

65°

340

+

22d

113

+

22

4.4

+

2.5

149

+

29

59

+

13

7.4

+

4.3

119

+

17

77

+

35

9.5

± 5.5

5

98

1865

+

103

682

+

123

245

+

30

156

+

14

620

+

118

222

+

48

95

+

17

678

+

125

245

+

34

161

± 17

1.0099

98

1849

+

96

131

+

39

0.3

+

0.3

86

+

86

48

+

31

25

+

6.2

15

+

7.8

0

+

0

0

+

0

450

± 17

2.3

98

1861

+

74

277

+

78

4.3

+

2.6

18

+

9

42

+

16

17

+

2.6

93

+

25

482

+

71

2.0

+

2.0

0

± 0

913

98

240

+

24

25

+

3.8

3

+

2.1

6.3

+

3.0

15

+

3.5

4

+

2.6

1

+

0.3

22

+

3.3

8

+

2.4

2.7

± 1.5

1

98

154

+

32

1.3

+

1.3

4.0

+

4.0

0

+

0

1.3

+

6.8

0

+

0

8.7

+

8.7

0

+

0

1 .3

+

1 .3

0

± 0

5

100

341

+

42

1.0

+

1.0

4.0

+

4.0

0

+

0

0

+

0

0

+

0

0

+

0

0

+

0

0

+

0

0

± 0

188

100

368

+

5.4

328

+

5.4

320

+

15.3

308

+

12

293

+

19

279

+

9.5

227

+

19

259

+

8.3

250

+

5.8

264

± 10

1336

100

319

+

13

337

+

13°

334

+

9.2°

252

+

26°

267

+

7.0

246

+

7.5

197

+

2.7

247

+

8.5

216

+

5.1

234

± 3.8

10

98

1423

+

30

1320

+

145°

1599

+

112°

1814

+

80'

1834

+

105°

1793

+

97°

1692

+

99°

1837

+

34°

1647

+

117°

1674

± 51°

16.8

1535

186

+

219

126

+

9.8°

127

+

8.7°

129

+

6.7°

198

+

5.5°

16

+

9.6

179

+

4.9°

225

+

11°

183

+

2.0°

209

± 22°

373

100

209

+

11

21

+

5.0

17

+

11

13

+

11

29

+

14

16

+

12

10

+

2.5

68

+

4.5

4

+

3.5

0

± 0

4098

100

215

+

16

48

+

3.5

24.0

+

12

22

+

4.5

25

+

2.5

16

+

2.5

19

+

19

44

+

2.0

2.5

+

2.5

0

± 0

TABLE 4 Effect of Green Tea Polyphenol P60A on the Mutagenicity of Reference Genotoxic Carcinogens3

Reference carcinogen ng/plate

Mutagenicity + SE

Carcinogen + polyphenon 60A (P60A)

Reference carcinogen ng/plate

2-Acetylaminofluorene

250

985 + 41.0

153.5 +

50.5a

17.5 + 4.5a

15.5 + 1.7a

10.0 + 1.0a

(AAF)

2-Aminoanthracene

5

1936 + 2.5

972 +

59.5a

166 + 66.0a

23.5 + 6.5a

12.5 + 1.5a

(AA)

2-Amino-3-methylimidazo-

0.5

1983 + 665

1765 +

67.5

323 + 43.0a

74.5 + 25.5a

14.0 + 8.0a

[4,5-f]quinoline (IQ)

Aflatoxin Bn (AFBn)

10

1288 + 121

73.5 +

28.3a

8.0 + 9.0a

7.5 + 0.5a

2.0 + 6.0a

Benzo[a]pyrene (BaP)

25

925 + 88

242 +

10.0a

51.5 + 11.5a

5.0 + 4.0a

0 + 0.5a

a Mutagenicity in Salmonella typhimurium strain TA98 for AAF, AF, IQ, and AFBq, and strain TA100 for BaP,p value of test versus revertants (rev)/platewithcarcinogenp < 0.05orbetter;dose-responsetrendp < 0.04forAAF + P60A;trendp < 0.008forAA + P60A;trendp < 0.006 for IQ + P60A; trendp < 0.04for AFB-, + P60A;trendp < 0.003 for BaP + P60A. Source: Ref. 33.

a Mutagenicity in Salmonella typhimurium strain TA98 for AAF, AF, IQ, and AFBq, and strain TA100 for BaP,p value of test versus revertants (rev)/platewithcarcinogenp < 0.05orbetter;dose-responsetrendp < 0.04forAAF + P60A;trendp < 0.008forAA + P60A;trendp < 0.006 for IQ + P60A; trendp < 0.04for AFB-, + P60A;trendp < 0.003 for BaP + P60A. Source: Ref. 33.

TABLE 5 MNU-induced Colon Tumors in F344 Rats Ingesting Green Tea Extract (GTE)

No. of

No. of rats

No. of tumors

No. of tumors

Groupsa

rats examined

with tumors

per rat

per tumor-bearing rat

Control

39

26 (67%)

1.2 + 0.2b

1.8 + 0.2b

HGTE

30

13 (43%)c

0.8 + 0.2

1.8 + 0.3

MGTE

30

12 (40%)c

0.5 + 0.1c

1.2 + 0.1c

LGTE

30

10 (33%)c

0.5 + 0.2c

1.5 + 0.4

a All rats were given an intrarectal dose of 2 mg of MNU 3 times a week for 2 weeks, and received either 0% (control group), 0.05% (hGTE group), 0.01% (mGTE group), or 0.002% (1GTE group) water solution of GTE as drinking water throughout the experiment. The experiment was terminated at week 35. b Mean = SEM.

c Significantly different from the control group: p < 0.05 or less. Source: Ref. 37.

a All rats were given an intrarectal dose of 2 mg of MNU 3 times a week for 2 weeks, and received either 0% (control group), 0.05% (hGTE group), 0.01% (mGTE group), or 0.002% (1GTE group) water solution of GTE as drinking water throughout the experiment. The experiment was terminated at week 35. b Mean = SEM.

c Significantly different from the control group: p < 0.05 or less. Source: Ref. 37.

oxidation of DNA, through the tobacco-carcinogen-associated formation of ROS, yielding as marker 8-OH-dG (46). In a model of colon cancer, black tea lowered oxidative damage to the colon (49) and epigallocatechin gallate had a synergistic effect with sulindac (50). Similar interactions were observed in genetically modified mice and the heterocyclic amine 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) (51). Inhibition was also demonstrated in APC (min) mice by this combination (52). Prostate cancer induction was decreased in TRAMP mice by green tea (53), and the molecular events were elucidated (54). The gene expression in human prostate LNCaP cells was altered (55).

We described above the formation of powerful mutagens during the cooking, frying, or broiling of meat, as heterocyclic aromatic amines. Epide-miological findings show that regular consumers of well-done cooked meat have a higher risk of cancer of the colon and breast (56-58). These are the target organs in rats, where cancer of the prostate and of the pancreas is also seen (59-62). The reason meats generate these kinds of compounds was discovered by a Swedish researcher, Jagerstad: namely, meats contain creatinine, which forms the 2-aminomethylimidazo part of the heterocyclic amines. Jagerstad's group developed an in vitro approach to model cooking, namely to heat glucose, creatinine, and an amino acid, such as glycine, or phenylal-anine (63). We have found that addition of black tea or green tea polyphenols and caffeine to meat inhibits the mutagenicity of heterocyclic amines (64). Also, based on that experiment, we and others have shown that addition of green tea or black tea polyphenols during the frying of ground meat prevents the formation of mutagenic heterocyclic amines, which seems to be a practical way to cook ''safe'' hamburgers (65,66).

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