Mutagenesis Advance Access originally published online on December 14, 2004
Mutagenesis 2005 20(1):23-28; doi:10.1093/mutage/gei002
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Mutagenesis vol. 20 no. 1 © UK Environmental Mutagen Society 2005; all rights reserved.
Black tea intake modulates the excretion of urinary mutagens in rats exposed to 6-aminochrysene: induction of cytochromes P450 by 6-aminochrysene in the rat
Molecular Toxicology Group, School of Biomedical and Molecular Sciences, University of Surrey, Guildford GU2 7XH, UK
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Abstract |
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Rats were exposed to black tea (2.5% w/v) as their sole drinking liquid for either 1 day (short-term) or 1 month (long-term), while controls received water. After exposure, all animals received a single oral dose of 6-aminochrysene and urine was collected for 72 h. Urinary mutagenicity was determined in the Ames test using an activation system comprising hepatic cytosol from Aroclor 1254-induced rats and utilizing the Salmonella typhimurium O-acetylase overexpressing bacterial strain YG1024. Both tea treatments suppressed the urinary excretion of indirect acting mutagens; no direct acting mutagenic activity was detectable. Furthermore, both tea treatments induced hepatic CYP1A2 activity, as exemplified by the O-demethylation of methoxyresorufin, when compared with the corresponding controls; similarly, an increase in CYP1A2 apoprotein levels was observed. The O-depentylation of pentoxyresorufin was also induced by the long-term tea treatment only, but the effect was less pronounced. No significant changes were seen in glutathione S-transferase and glucuronosyl transferase activities. When rats were exposed to caffeine at a dose level corresponding to that in black tea, a marked decrease was observed in the urinary excretion of indirect acting mutagens following a single oral dose of 6-aminochrysene. It is concluded that even after short-term exposure, black tea enhances the metabolism of 6-aminochrysene and that this is probably related to the up-regulation of hepatic CYP1A2 by the caffeine present in black tea. Finally, 6-aminochrysene was a potent inducer of CYP1A1, as assessed by the O-deethylation of ethoxyresorufin and immunoblot analysis. The same treatment modestly increased glutathione S-transferase activity when assessed using 1-chloro-2,4-dinitrobenzene as the accepting substrate.
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Introduction |
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The anticarcinogenic activity of tea, both green and black, has been amply demonstrated in animal studies (Wang et al., 1992
, 1994; Gupta et al., 2001; Li et al., 2002), but extensive epidemiological studies have failed to provide unequivocal evidence for its effectiveness in humans (Kohlmeier et al., 1997; Yang et al., 2002).
One of the principal mechanisms of the anticarcinogenic activity of tea is inhibition of the initiation stage of carcinogenesis. Indeed, in studies employing various mutagenicity end-points, in particular the Ames test, it was clearly established that aqueous tea extracts suppress the mutagenic activity of major classes of chemical carcinogens of relevance to humans, especially of those which are indirect acting (Bu-Abbas et al., 1996; Catterall et al., 1998; Ioannides and Yoxall, 2003), i.e. necessitating metabolic bioactivation in order to express their carcinogenicity. Similarly, tea prevented the binding of carcinogenic compounds to DNA (Xu et al., 1996; Schut and Yao, 2000). Disruption of the delicate balance of metabolic activation and detoxification of chemical carcinogens is a process that may facilitate such an effect. Enhanced detoxification, at the expense of bioactivation, will lead to reduced availability of the DNA-binding metabolites of carcinogens. We have presented evidence (McArdle et al., 1999) that exposure to green or black tea, but not decaffeinated tea, for 1 month decreased the excretion of direct and indirect acting mutagens in the urine of rats treated with a single oral dose of the heterocyclic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). The subsequent studies of Embola et al. (2001a,b) revealed that green tea at least, when administered to rats for 6 weeks, altered the metabolism of this carcinogen so as to favour detoxification pathways, explaining the tea-mediated changes in urinary mutagens. In more recent studies (Yoxall et al., 2004) we have demonstrated that black tea, even when administered for a single day before exposure to a single dose of IQ, suppressed the excretion of mutagens in the urine of animals, and this effect was related to the up-regulation of CYP1A2, the principal cytochrome P450 enzyme catalysing the metabolism of this carcinogen (Turesky, 2002).
The principal objectives of the current study were two-fold. First, to investigate whether the effect of tea on the metabolism of chemical carcinogens, as exemplified by the urinary excretion of mutagens, extends beyond heterocyclic amines to other chemical carcinogens, in this case 6-aminochrysene, and, secondly to establish the duration of tea intake required for such an effect to be manifested. Finally, we took this opportunity to evaluate the effect of 6-aminochrysene on the expression of hepatic cytochrome P450 enzymes in the rat.
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Materials and methods |
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1,2-Dichloro-4-nitrobenzene (DCNB) (Aldrich Chemical Co. Ltd, Gillingham, UK), nucleotide cofactors (Melford Laboratories Ltd, Ipswich, Suffolk) and
-naphthol, -naphthol-ß-glucuronide, resorufin and alkoxyresorufins, 6-aminochrysene, glutathione, glutathione reductase, 1-chloro-2,4-dinitrobenzene (CDNB), UDP-glucuronic acid, adenosine 3'-phosphate 5'-phosphosulphate, ß-glucuronidase, D-saccharic acid-1,4-lactone, sulphatase and peroxidase-linked anti-sheep IgG (Sigma Co. Ltd, Poole, UK) were all purchased. Black tea (Keemun) was purchased locally and stored at 4°C in a sealed bag. Antibodies to CYP1A, recognizing both enzymes within this subfamily, were raised in sheep using rat CYP1A1 as antigen (Rodriguez et al., 1987). Male Wistar albino rats (120–150 g), obtained from B & K Universal Ltd (Hull, UK), were used in all studies. The activation system was derived from rats treated with a single i.p. dose of Aroclor 1254 (500 mg/kg), the animals being killed on day 5 following administration. Black tea infusions (2.5% w/v) were prepared by adding boiling water (400 ml) to the tea (10 g) in a prewarmed thermos flask, leaving to stand for 10 min with inversion every 30 s and then filtering through cotton wool. The brew was allowed to stand overnight at 4°C to allow the tea to cream fully.
A preliminary study was first carried out whose objectives were: (i) to establish whether urinary excretion of mutagens following administration of 6-aminochrysene is dose-dependent; (ii) to establish the time profile for urinary excretion of mutagens following 6-aminochrysene administration; (iii) to identify the most efficient activation system for 6-aminochrysene in the Ames mutagenicity assay; (iv) to evaluate the effect of the deconjugating enzymes sulphatase and glucuronidase on the urinary mutagenic response. Rats were treated with a single dose of 10, 20, 50 or 100 mg/kg of 6-aminochrysene, dissolved in corn oil, by gastric intubation and urine was collected for 72 h. Deconjugation was performed by incubating the urine sample with an equal volume of 0.2 M sodium acetate buffer, pH 5, containing ß-glucuronidase (5000 U/ml), sulphatase (250 U/ml) supplemented with D-saccharic acid-1, 4-lactone or a mixture of the two enzymes at 37°C for 16 h.
To assess the effect of black tea on urinary mutagenicity the following experimental design was adopted. Four groups of rats each comprising four animals were used. One group served as a control, one group received a single oral dose (50 mg/kg) of 6-aminochrysene only, while the other two were maintained on 2.5% (w/v) aqueous black tea extracts as their sole source of liquid for either 1 day or 1 month and 24 h later were given a single dose of 6-aminochrysene (50 mg/kg) by gastric intubation. Urine was collected prior to and for 72 h after carcinogen administration. On completion of urine collection the animals were killed by cervical dislocation, the livers were immediately excised and post-mitochondrial (S9) fractions were prepared and stored at –20°C until use.
Finally, in a separate study, the effect of caffeine administration on the excretion of mutagens in rats was investigated. Two groups of rats, comprising five animals each, were used. One was maintained on caffeine in the drinking water (700 mg/l) for 1 day while the other served as a control, and 24 h later both groups were given a single dose of 6-aminochrysene (50 mg/kg) by gastric intubation. Urine was collected prior to and for 72 h after carcinogen administration. The concentration of caffeine is based on the levels found in the Keemun black tea (McArdle et al., 1999).
Mutagenic activity was monitored using the Ames mutagenicity assay (Maron and Ames, 1983) in the presence and absence of a 10% (v/v) activation system derived from Aroclor 1254-induced rats and employing Salmonella typhimurium strain YG1024. Urine samples were centrifuged at 2000 g for 10 min and the supernatant was stored at –20°C until used. For determination of the excretion of indirect acting mutagens, 200 µl aliquots were employed in the Ames test. It is relevant to emphasize that in these studies urine was not concentrated; at the levels used in the Ames test it has been established that rat urine influences neither the spontaneous reversion rate nor the mutagenic activity induced by chemicals (McArdle et al., 1999).
For the determination of xenobiotic-metabolizing enzymes, the S9 fractions were allowed to thaw and subjected to centrifugation at 105 000 g for 1 h, to separate microsomes from the soluble fraction. Using the resuspended microsomes the O-dealkylation of methoxyresorufin (Burke and Mayer, 1983), ethoxyresorufin (Burke and Mayer, 1974), pentoxyresorufin (Lubet et al., 1985), and glucuronosyl transferase using -naphthol as substrate (Bock and White, 1974) were determined. Assays for glutathione S-transferase activity using DCNB and CDNB as substrates (Habig et al., 1974) were carried out on the cytosolic fraction. Protein was determined in both microsomal and cytosolic fractions using the Lowry procedure (Lowry et al., 1951). Finally, in order to determine CYP1A apoprotein levels, hepatic microsomal proteins were resolved by electrophoresis and incubated with rat anti-CYP1A1, raised in sheep, followed by peroxidase-linked anti-sheep IgG.
Statistical evaluation was carried out using Student's t-test.
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Results |
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Hepatic cytosol from Aroclor 1254-treated rats was far more effective than the corresponding S9 fraction in activating 6-aminochrysene in the Ames test; of the two S.typhimurium strains, a higher mutagenic response was observed with YG1024 (Figure 1). When the mutagenicity of rat urine following exposure to 6-aminochrysene was investigated, the deconjugating enzymes ß-glucuronidase and sulphatase failed to enhance the mutagenic response (Table I). Following treatment of the rats with a single oral dose of 6-aminochrysene (100 mg/kg) most of the mutagenic activity, determined in the presence of an activation system, was excreted in the urine within 24 h, with only traces of mutagenic activity being present in the urine 72 h following administration (Figure 2). No mutagenic response was detectable in the absence of an activation system. A study undertaken to establish whether urinary excretion of mutagenicity is dose-dependent revealed a linear response up to a dose of 50 mg/kg 6-aminochrysene, but at the higher dose of 100 mg/kg the mutagenic response was markedly higher than anticipated (Figure 3).
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Maintenance of the animals on black tea as their sole drinking water for 1 month had no obvious adverse effect and body weight gain was similar to that seen in control animals (results not shown). Urinary mutagenicity, assessed in the presence of an activation system, decreased following exposure of the animals to black tea, whether for 1 day or 1 month, but a wide variation was observed and statistical significance was not reached (Figure 4). A decline in the urinary excretion of mutagens as a result of black tea intake was seen in the 24 and 48 h samples. Exposure of rats to caffeine caused a very marked, and statistically significant (P < 0.001), decrease in the urinary excretion of indirect acting mutagens during the first 24 h following carcinogen administration (Figure 5).
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Treatment of rats with a single oral dose of 6-aminochrysene markedly stimulated the O-deethylation of ethoxyresorufin with no significant effect on the O-demethylation of methoxyresorufin (Table II). When rats were treated with black tea in addition to 6-aminochrysene there were no effects on the O-deethylation of ethoxyresorufin, when compared with animals treated with the carcinogen only (Table II). However, in the case of the O-demethylation of methoxyresorufin both short- and long-term exposure to tea significantly induced this enzyme activity compared with animals treated with the carcinogen only (Table II). A rise in the O-depentylation of pentoxyresorufin was evident in the animals receiving both 6-aminochrysene and black tea for 1 month.
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Immunoblot analysis employing antibodies to CYP1A1 showed that exposure to 6-aminochrysene selectively enhanced CYP1A1 apoprotein levels, but in the animals receiving both tea and carcinogen both CYP1A1 and CYP1A2 apoprotein levels were increased (Figure 6).
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Treatment with 6-aminochrysene had no effect on cytosolic glutathione S-transferase activity when monitored using DCNB as the accepting substrate, but when CDNB was used treatment with 6-aminochrysene either alone or with tea caused a modest, but statistically significant, rise in activity (Table II). Finally, glucuronosyl activity was elevated only in the animals receiving a combination of tea for 1 month and a single dose of 6-aminochrysene (Table II).
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Discussion |
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We have demonstrated in previous studies that exposure to black tea, for either 1 day or 1 month, suppressed the excretion of both direct and indirect acting mutagens in the urine of rats treated with a single dose of IQ; this effect appears to be related to a rise in CYP1A2 expression in the liver (McArdle et al., 1999
; Yoxall et al., 2004). These studies have been undertaken to investigate whether this effect of tea is confined to heterocyclic amines such as IQ or extends to other major classes of chemical carcinogens. Our initial intention was to employ unsubstituted polycyclic aromatic hydrocarbons, such as benzo[a]pyrene. Even when high doses were employed (100 mg/kg), no mutagenic response could be detected either in the presence or absence of an activation system derived from the liver of Aroclor 1254-induced rats (results not shown). It became obvious that in order for a mutagenic response to be detected, a substituted polycyclic aromatic hydrocarbon, possibly with a nitro or an amino group had to be utilized. We chose 6-aminochrysene, a mutagen which we had used extensively in previous studies. The bioactivation of this carcinogen through N-hydroxylation is catalysed not only by microsomal cytochrome P450 enzymes, but also by a distinct cytosolic amine oxidase that is inducible by Aroclor 1254 (Marczylo and Ioannides, 1994, 1998). Preliminary studies were undertaken to establish which enzyme system is the most effective in catalysing the bioactivation of 6-aminochrysene, thus allowing high mutagenic activity to be detected in the urine of animals treated with this carcinogen. The cytosolic preparations were far more effective than the corresponding S9 preparations in activating 6-aminochrysene to mutagens in the Ames test. Of the two S.typhimurium bacterial strains employed, the mutagenic activity was orders of magnitude higher in the O-acetylase expressing strain YG1024, confirming our previous findings that the cytosol-mediated bioactivation of this carcinogen proceeds through N-hydroxylation to yield the hydroxylamine which, following conjugation with acetate, generates the acetoxy ester that breaks down to the ultimate carcinogen, believed to be the nitrenium ion (Marczylo and Ioannides, 1994). In order to further enhance the mutagenic activity, we considered the incorporation of a preincubation step; no increase in mutagenic response was evident with up to a 90 min preincubation (results not shown). Treatment of the urine from 6-aminochrysene-treated rats with the deconjugating enzymes ß-glucuronidase and sulphatase failed to increase mutagenic activity, implying that no such conjugates of the mutagenic intermediates were excreted in the urine or, alternatively, such conjugates are not good substrates for the deconjugating enzymes. Consequently, in the current studies urine was not treated with deconjugating enzymes. Similar observations were made when IQ served as the model mutagen (McArdle et al., 1999). Following the administration of 6-aminochrysene most of the mutagenic activity, assessed in the presence of an activation system, was found in the first 24 h urine sample; relatively very little mutagenic activity was present in the 48 h sample and only traces of activity were evident in the 72 h sample. Consequently, in all subsequent studies urine was collected for 72 h following carcinogen administration. In studies aimed at establishing a dose–response relationship between oral 6-aminochrysene administration and urinary mutagenicity, rats were treated with a range of doses (10–100 mg/kg). A dose-dependent increase in urinary mutagenicity was observed, however, at the highest carcinogen dose employed the urinary mutagenic activity was markedly higher than anticipated. Clearly, saturation of either the carcinogen metabolic processes has occurred at this dose level and/or of transporters that may limit the absorption of this carcinogen. In the subsequent experimental studies a dose of 50 mg/kg was utilized.
Having established the conditions for obtaining a maximum mutagenic response, the effect of black tea on the mutagenic response was investigated. A black tea brew was supplied to the animals as the sole drinking liquid for either 1 day or 1 month. Both treatments decreased urinary mutagenicity. These findings imply that treatment has stimulated metabolism of the carcinogen, resulting in lower excretion of the parent compound. It is possible that other metabolites with an intact amino group may have been excreted and contributed to the mutagenic activity, but this is unlikely since ring-hydroxylated metabolites of other carcinogenic amino compounds, such as 4-aminobiphenyl and ß-naphthylamine, could not be metabolically converted to mutagenic products (Tong et al., 1986; Ioannides et al., 1989). It should be pointed out that mutagenic epoxides and diol epoxides are unlikely to be found intact in urine as they are highly reactive and unlikely to survive passage into the urine and are also effectively detoxified by epoxide hydrolase and glutathione S-transferases. Indeed, when benzo[a]pyrene was administered to rats, no mutagenic activity was detectable in urine (results not shown).
The microsomal metabolism of 6-aminochrysene involves the CYP1 family, in particular the enzymes CYP1A1 and CYP1B1, which appear to catalyse arene oxidation; these are constitutively poorly expressed in the liver but are, however, inducible. The CYP2B subfamily is, however, the principal catalyst of the N-hydroxylation pathway in both rats and humans (Yamazaki and Shimada, 1992; Yamazaki et al., 1993). The contribution of the cytosolic amine oxidase to the in vivo metabolism of 6-aminochrysene remains to be evaluated. Intake of black tea, for either 1 day or 1 month, selectively elevated the levels of hepatic CYP1A2, confirming our previous observations (Bu-Abbas et al., 1999; Yoxall et al., 2004). Bearing in mind the role of this enzyme in the metabolism of 6-aminochrysene, it may be inferred that a rise in the levels of this enzyme facilitates metabolism of the carcinogen, leading to lower levels excreted intact in the urine. However, it should be pointed out that when the animals were maintained on tea for only 1 day, xenobiotic-metabolizing enzymes were determined when urinary excretion of mutagens was complete, i.e. not at the time of 6-aminochrysene administration but 72 h afterwards, during which time the animals were still drinking tea. It may, consequently, be argued that CYP1A2 activity was overestimated in our studies, as it was not determined at the time of carcinogen exposure. It is our view that this is highly unlikely since the urinary excretion of mutagens was markedly suppressed during the first 24 h after 6-aminochrysene administration. Following intake of black tea, a modest and statistically significant rise in the O-depentylation of pentoxyresorufin was observed, an activity associated with CYP2B activity (Namkung et al., 1988). Since this subfamily is also believed to be involved in the metabolism of 6-aminochrysene, it is conceivable that it may also contribute to the enhanced metabolism of this carcinogen seen after long-term tea exposure. The rise in CYP1A2 and CYP2B activities following treatment with black tea appears to be due to the high caffeine concentration in tea (Chen et al., 1996; Bu-Abbas et al., 1999), an established inducer of these cytochrome P450 enzymes (Ayalogu et al., 1995). During the long-term intake of tea, combined treatment with 6-aminochrysene led to a significant rise in glucuronosyl transferase activity, determined using -naphthol as substrate, but no such effect was evident during short-term exposure to tea. It may be inferred that this enzyme is not responsible for the black tea-mediated decrease in urinary mutagenicity. Cytosolic glutathione S-transferase activity when assessed using CDNB or DCNB as the substrate was unaffected by the tea plus 6-aminochrysene treatment when compared with animals receiving the carcinogen only.
In order to establish the role of caffeine, an additional study was conducted where black tea was replaced with the corresponding amount of caffeine. Even after only a single day of intake, caffeine caused a very marked decrease in the urinary excretion of mutagens, confirming its contribution to the effects elicited by black tea. The fact that the effect of caffeine alone was more pronounced than that of black tea may reflect a lower bioavailability of caffeine when consumed with tea.
Finally, in these studies it was observed that 6-aminochrysene, even after only a single oral administration, was a potent inducer of CYP1A1, as exemplified by an increase in ethoxyresorufin O-deethylation, a probe associated with this enzyme (Namkung et al., 1988), and a marked rise in CYP1A1 apoprotein levels. Similar observations have been reported for non-substituted chrysene and its methyl and benzo derivatives (Cheung et al., 1993). Furthermore, the same treatment modestly increased glutathione S-transferase activity, but only when assessed using CDNB as substrate.
In conclusion, it was demonstrated in these studies that both short- and long-term intake of black tea diminishes the excretion of indirect acting mutagens in rats treated with 6-aminochrysene; this appears to be largely associated with elevation of hepatic CYP1A2, which may lead to enhanced metabolism of the carcinogen. Finally, 6-aminochrysene is a potent and selective inducer of CYP1A1 in rat liver.
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Acknowledgments |
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The authors gratefully acknowledge financial support from the European Union under Framework 4 (POLYBIND project).
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* To whom correspondence should be addressed. Tel: +44 1483 689709; Fax: +44 1483 576978; Email: c.ioannides{at}surrey.ac.uk
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References |
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Ayalogu,E.O., Snelling,J., Lewis,D.F.V., Talwar,S., Clifford,M.N. and Ioannides,C. (1995) Induction of hepatic CYP1A2 by the oral administration of caffeine to rats: Lack of association with the Ah locus. Biochim. Biophys. Acta, 1272, 89–94.[Medline]
Bock,K.W. and White,I.N.H. (1974) UDP-glucuronyltransferase in perfused rat liver and in microsomes: influence of phenobarbital and 3-methylcholanthrene. Eur. J. Biochem., 46, 451–459.[ISI][Medline]
Bu-Abbas,A., Nunez,X., Clifford,M.N., Walker,R. and Ioannides,C. (1996) A comparison of the antimutagenic potential of green, black and decaffeinated teas: contribution of flavanols to the antimutagenic effect. Mutagenesis, 11, 597–603.
Bu-Abbas,A., Clifford,M.N., Walker,R. and Ioannides,C. (1999) Modulation of hepatic cytochrome P450 activity and carcinogen bioactivation by tea: contribution of caffeine and flavanols. Environ. Toxicol. Pharmacol., 7, 41–47.
Burke,M.D. and Mayer,R.T. (1974) Ethoxyresorufin: direct fluorimetric assay of a microsomal O-dealkylation which is preferentially inducible by 3-methylcholanthrene. Drug Metab. Dispos., 2, 583–588.[Abstract]
Burke,M.D. and Mayer,R.T. (1983) Differential effects of phenobarbitone and 3-methylcholanthrene induction on the hepatic microsomal cytochrome P450-binding of phenoxazone and an homologous series of its n-alkyl ethers (alkoxyresorufins). Chem. Biol. Interact., 45, 243–258.[CrossRef][ISI][Medline]
Catterall,F., Copeland,E., Clifford,M.N. and Ioannides,C. (1998) Contribution of theafulvins to the antimutagenicity of tea. Mutagenesis, 13, 631–636.
Chen,L., Bondoc,F.Y., Hussin,A.H.J., Thomas,P.E. and Yang,C.S. (1996) Caffeine induces cytochrome P4501A2: induction of CYP1A2 by tea in rats. Drug Metab. Dispos., 24, 529–533.[Abstract]
Cheung,Y.-L., Gray,T.J.B. and Ioannides,C. (1993) Mutagenicity of chrysene, its methyl and benzo derivatives and their interactions with cytochromes P-450 and the Ah receptor; relevance to their carcinogenic potency. Toxicology, 81, 69–86.[CrossRef][ISI][Medline]
Embola,C.W., Weisburger,J.H. and Weisburger,M.C. (2001a) Urinary excretion of N-OH-2-amino-3-methylimidazo[4,5-f]quinoline-N-glucuronide in F344 rats is enhanced by green tea. Carcinogenesis, 22, 1095–1098.
Embola,C.W., Weisburger,M.C. and Weisburger,J.H. (2001b) Green tea and the metabolism of 2-amino-3-methylimidazo[4,5-f]quinoline in F344 rats. Food Chem. Toxicol., 39, 629–633.[CrossRef][ISI][Medline]
Gupta,S., Hastak,K., Ahmad,N., Lewin,J.S. and Mukhtar,H. (2001) Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols. Proc. Natl Acad. Sci. USA, 98, 10350–10355.
Habig,W.H., Pabst,M.J. and Jakoby,W.B. (1974) Glutathione S-transferase, the first enzymic step in mercapturic acid formation. J. Biol. Chem., 249, 7130–7139.
Ioannides,C. and Yoxall,V. (2003) Antimutagenic activity of tea: role of polyphenols. Curr. Opin. Clin. Nutr. Metab. Care, 6, 649–656.[ISI][Medline]
Ioannides,C., Lewis,D.F.V., Trinick,J., Neville,S., Sertkaya,N.N., Kajbaf,M. and Gorrod,J.W. (1989) A rationale for the non-mutagenicity of 2- and 3-aminobiphenyls. Carcinogenesis, 10, 1403–1407.
Kohlmeier,L., Weterings,K.G.C., Steck,S. and Kok,F.J. (1997) Tea and cancer prevention: an evaluation of the epidemiologic literature. Nutr. Cancer, 27, 1–13.[ISI][Medline]
Li,N., Chen,X., Liao,J. et al. (2002) Inhibition of 7,12-dimethylbenz[a] anthracene (DMBA)-induced oral carcinogenesis in hamsters by tea and curcumin. Carcinogenesis, 23, 1307–1313.
Lowry,O.H., Rosebrough,N.J., Farr,A.L. and Randall,R.J. (1951) Protein measurement with the Folin phenol reagent. J. Biol. Chem., 193, 265–275.
Lubet,R.A., Mayer,R.T., Cameron,J.W., Nims,R.N., Burke,M.D., Wolf,T. and Guengerich,F.P. (1985) Dealkylation of pentoxyresorufin: a rapid and sensitive assay for measuring induction of cytochrome(s) P450 by phenobarbital and other xenobiotics in the rat. Arch. Biochem. Biophys., 238, 43–48.[CrossRef][ISI][Medline]
Maron,M.D. and Ames,B.N. (1983) Revised methods for the Salmonella mutagenicity test. Mutat. Res., 113, 173–215.[CrossRef][ISI][Medline]
Marczylo,T. and Ioannides,C. (1994) Bioactivation of 6-aminochrysene by animal and human hepatic preparations: contributions of microsomal and cytosolic enzyme systems. Mutagenesis, 9, 233–239.
Marczylo,T. and Ioannides,C. (1998) The substrate specificity of the rat hepatic cytosolic arylamine oxidase catalysing the bioactivation of aromatic amines. Cancer Lett., 127, 141–146.[CrossRef][ISI][Medline]
McArdle,N.J., Clifford,M.N. and Ioannides,C. (1999) Consumption of tea modulates the urinary excretion of mutagens in rats treated with IQ: role of caffeine. Mutat. Res., 441, 191–203.[ISI][Medline]
Namkung,M.J., Yang,H.L., Hulla,J.E. and Juchau,M.R. (1988) On the substrate specificity of cytochrome P450IIIA1. Mol. Pharmacol., 34, 628–637.[Abstract]
Rodrigues,A.D., Gibson,G.G., Ioannides,C. and Parke,D.V. (1987) Interactions of imidazole antifungal agents with purified cytochrome P450 proteins. Biochem. Pharmacol., 36, 4277–4281.[CrossRef][ISI][Medline]
Schut,H.A.J. and Yao,R. (2000) Tea as a chemopreventive agent in PhIP carcinogenesis: effects of green tea and black tea on PhIP–DNA adduct formation in female F-344 rats. Nutr. Cancer, 36, 52–58.[CrossRef][ISI][Medline]
Tong,S., Smith,J., Manson,D., Gorrod,J.W. and Ioannides,C. (1986) The metabolic activation of 2-naphthylamine to mutagens in the Ames test. Anticancer Res., 6, 1107–1112.[ISI][Medline]
Turesky,R.J. (2002) Heterocyclic aromatic amine metabolism, DNA adduct formation, mutagenesis and carcinogenesis. Drug Metab. Rev., 34, 625–650.[CrossRef][ISI][Medline]
Wang,Z.Y., Hong,J.Y., Huang,M.-T., Reuhl.K.R., Conney,A.H. and Yang,C.S. (1992) Inhibition of N-nitrosodiethylamine- and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced tumorigenesis in A/J mice. Cancer Res., 52, 1943–1947.
Wang,Z.Y., Huang,M.-T., Lou,Y.-R., Xie,J.-G., Reuhl,K.R., Newmark,H.L., Ho,C.-T., Yang,C.S. and Conney,A.H. (1994) Inhibitory effects of black tea, green tea, decaffeinated black tea and decaffeinated green tea on ultraviolet B light-induced skin tumorigenesis in 7,12-dimethylbenz(a)anthracene-initiated SKH-1 mice. Cancer Res., 54, 3428–3435.
Xu,M., Bailey,A.C., Hernaez,J.F,. Taoka,C.R., Schut,H.A.J. and Dashwood,R.H. (1996) Protection by green tea, black tea and indole-3-carbinol against 4-methylimidazo[4,5-f]quinoline-induced DNA adducts and colonic aberrant crypts in the F344 rat. Carcinogenesis, 17, 1429–1434.
Yamazaki,H. and Shimada,T. (1992) Activation of 6-aminochrysene to genotoxic products by different forms of rat liver cytochrome P450 in the O-acetyltransferase-overexpressing Salmonella typhimurium strain (NM2009). Biochem. Pharmacol., 44, 913–920.[CrossRef][ISI][Medline]
Yamazaki,H., Mimura,M., Oda,Y., Inui,Y., Shiraga,T., Guengerich,F.P. and Shimada,T. (1993) Role of different forms of cytochrome P450 in the activation of the promutagen 6-aminochrysene to genotoxic metabolites in human liver microsomes. Carcinogenesis, 14, 1271–1278.
Yang,C.S., Maliakal,P. and Meng,X. (2002) Inhibition of carcinogenesis by tea. Annu. Rev. Pharmacol. Toxicol., 42, 25–54.[CrossRef][ISI][Medline]
Yoxall,V.R., Parker,D.A., Kentish,P.A. and Ioannides,C. (2004) Short-term black tea intake modulates the excretion of urinary mutagens in IQ-treated rats: role of CYP1A2 up-regulation. Arch. Toxicol., 78, 477–482.[ISI][Medline]
Received on June 1, 2004; revised on October 28, 2004; accepted on November 4, 2004.
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