Mutagenesis, Vol. 18, No. 2, 145-150,
March 2003
© 2003 UK Environmental Mutagen Society/Oxford University Press
Effects of black tea theafulvins on aflatoxin B1 mutagenesis in the Ames test
School of Biomedical and Life Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK
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Abstract |
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Black tea theafulvins, a fraction of thearubigins isolated from black tea aqueous infusions, potentiated the mutagenic activity of the mycotoxin aflatoxin B1 in the Ames test, in the presence of a hepatic S9 activation system derived from Aroclor 1254-treated rats. In contrast, when the S9 activation system was replaced with isolated microsomes, theafulvins suppressed the mutagenicity of the mycotoxin. When microsomal metabolism was terminated after metabolic activation of the mycotoxin, incorporation of the theafulvins into the activation system reduced the mutagenic activity, whereas if it was added before termination of microsomal activity a potentiation of mutagenic response was observed. In in vitro studies, theafulvins inhibited epoxide hydrolase and glutathione S-transferase activities in a concentration-dependent manner. Finally, the mutagenicity of aflatoxin B1 was much more pronounced in bacteria that were pre-exposed to theafulvins but from which they were subsequently washed off. It may be inferred from the above studies that the genotoxic synergy between aflatoxin B1 and black tea theafulvins does not occur during the bioactivation of the carcinogen, but may partly be due to decreased deactivation of the reactive intermediate, aflatoxin B1 8,9-oxide, by conjugation with glutathione.
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Introduction |
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An ever increasing number of experimental studies conducted in animal models have established that aqueous tea extracts, at concentrations similar to those consumed by humans, can effectively antagonize the carcinogenicity of many, structurally diverse chemicals (Ahmad et al., 1998
; Yang et al., 2001). Although most of the initial studies employed green teas, the types preferred in China and Japan, a number of studies revealed that black teas, the types most extensively consumed in the Western hemisphere, also possess similar anticarcinogenic properties against spontaneous and chemical- and radiation-induced cancers in experimental animals (Wang et al., 1993, 1994; Landau et al., 1998; Lu et al., 2001). Thus it is becoming increasingly evident that tea, one of the most extensively consumed beverages, is a potential major human anticarcinogen.
An important characteristic of the anticarcinogenic action of tea is its ability to beneficially modulate all stages of chemical carcinogenesis, namely initiation (Bu-Abbas et al., 1994, 1996) and the post-initiation processes of promotion and progression (Huang et al., 1992; Lea et al., 1993; Wang et al., 1994; Lu, 1997; Yang et al., 1998). Three possible mechanisms may be responsible for the suppression of the initiation stage of carcinogenesis, namely inhibition of the bioactivation of the chemical carcinogens, scavenging of the reactive intermediates (Bu-Abbas et al., 1994, 1996) and enhanced Phase II deactivation by enzymes such as the glucuronosyl and glutathione transferases (Sohn et al., 1994; Bu-Abbas et al., 1995, 1998). The ability of tea to inhibit post-initiation processes has been attributed to the strong antioxidant activity of many of its constituents (Yang and Wang, 1993; Shiraki et al., 1994; Miller et al., 1996).
The constituent(s) of black tea responsible for its anticarcinogenic properties have not so far been identified. During the fermentation of green tea to produce black tea, polyphenol oxidases convert some two-thirds of the green tea flavanols to reddish-brown pigments, the two major groups being theaflavins and thearubigins. Both of these classes of black tea polyphenols have been shown to suppress the mutagenicity of various promutagens (Weisburger et al., 1996; Apostolides et al., 1997). In more recent studies emanating from our laboratory (Catterall et al., 1998), it was established that theafulvins, a fraction of thearubigins, suppressed the mutagenicity of indirect-acting carcinogens and could account to a large extent for the antimutagenic activity of black tea. Moreover, black tea theaflavins could afford protection against the pulmonary carcinogenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in mice (Yang et al., 1997) and the oesophageal carcinogenicity of N-nitrosomethylbenzylamine in rats (Morse et al., 1997). Recent studies performed using human lung and colon cancer lines revealed that theaflavins inhibit growth and induce apoptosis (Yang et al., 1998) and impair transformation in murine epidermal cells (Dong et al., 1997), suggesting that such mechanisms may contribute to the anticarcinogenic effect of tea occurring at the post-initiation stage.
Our studies focused on black tea theafulvins, a fraction of thearubigins, which are a major polyphenolic component of black tea (Bailey et al., 1992; Powell, 1995). As already noted, we demonstrated that theafulvins possess potent antimutagenic activity against indirect-acting food carcinogens such as heterocyclic amines, polycyclic aromatic hydrocarbons and N-nitrosamines (Catterall et al., 1998). Surprisingly, however, theafulvins potentiated the mutagenic activity of the mycotoxin aflatoxin B1, and the present study was undertaken to elucidate the underlying mechanisms.
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Materials and methods |
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Aflatoxin B1, 1-chloro-2,4-dinitrobenzene (CDNB), 3,4-dichloronitrobenzene (DCNB) and all cofactors were purchased from Sigma Chemical Co. (Poole, UK), whereas benzo[a]pyrene 4,5-dihydrodiol and benzo[a]pyrene 4,5-epoxide were purchased from Mid-West Research Institute. Theafulvins were isolated from aqueous infusions of black tea (Lattakari Assam) as previously described (Bailey et al., 1992
). Infusions of tea were first decaffeinated using chloroform extraction and then partitioned against ethyl acetate. Theaflavins were extracted into the organic solvent but the thearubigins remained in the aqueous phase. Theafulvins were separated from the other thearubigins by passing the crude thearubigin fraction through a Solka floc cellulose column from which the theafulvins were eluted using 50% acetone (v/v) in water. They have apparent masses in the range 900–2300 Da when the column is calibrated with pure neutral condensed and hydrolysable tannins (Powell, 1995). Their concentration in black tea ranges from 0.3 to 3.0 mg/ml depending on the method of brewing.
Male Wistar albino rats (120–150 g), obtained from Harlan Olac (Bicester, UK), were used in all studies. Induction of the CYP1 family was achieved by administration of a single i.p. dose of Aroclor 1254 (500 mg/kg), the animals being killed on day 5 following administration. Hepatic post-mitochondrial (S9), microsomal and cytosolic fractions were prepared as previously described (Ioannides and Parke, 1975). Mutagenic activity was monitored using the Ames mutagenicity assay (Maron and Ames, 1983). When isolated microsomes were used, the activation system was supplemented with glucose 6-phosphate dehydrogenase (1 U/plate).
In order to assess whether theafulvins interact with the electrophilic intermediates of aflatoxin B1, the Ames procedure was modified as previously described (Catterall et al., 1998). Initially, the bacteria, carcinogen and activation system were preincubated for 20 min in a shaking water bath at 37°C. Microsomal metabolism was terminated by the addition of 100 µl of menadione (900 µM) and a second 20 min preincubation was carried out in the presence of theafulvins. Top agar was added and the mixture was poured onto minimal agar plates that were incubated for 48 h at 37°C to allow revertants to develop into colonies.
In studies aimed at investigating whether the effect of theafulvins on aflatoxin B1 mutagenicity is mediated through an effect on the bacteria that renders them more mutable, a different experimental design was employed. Bacteria were inoculated and allowed to grow in nutrient broth containing black tea theafulvins (180 µg/ml; this concentration corresponds to that employed in the Ames test studies). Prior to using these bacteria in the Ames test, theafulvins were removed by precipitating the bacteria by centrifugation (3500 g for 5 min) and resuspending them in fresh nutrient broth (10 ml). This procedure was repeated for a further two times to ensure that the theafulvins were washed away.
All mutagenicity studies were repeated at least once and results were reproducible.
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Results |
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Black tea theafulvins, at least up to a concentration of 500 µg/plate, did not elicit a mutagenic response in S.typhimurium TA98, either in the presence or absence of an activation system derived from Aroclor 1254-induced rats; under the same conditions the positive controls, 2-aminoanthracene in the presence of the activation system and N'-methyl-N'-nitro-N-nitrosoguanidine in the absence of the activation system, induced the expected mutagenic response (results not shown).
Aflatoxin B1, at a concentration range of 1–5 µg/plate, induced a mutagenic response in the presence of an S9 activation system (Figure 1). At all concentrations of the mutagen, theafulvins markedly potentiated the mutagenic response. Potentiation of the aflatoxin B1 mutagenicity appears to be dependent on the theafulvin concentration; with the exception of the lowest aflatoxin B1 concentration used, i.e. 1 µg/plate, the increase in mutagenicity of the mycotoxin was higher in the presence of a 200 µg/plate concentration of theafulvin compared with 50 µg/plate (Figure 1). In order to evaluate whether the theafulvin-mediated stimulation of aflatoxin B1 mutagenicity involved microsomal and/or cytosolic factors of the liver, further studies where undertaken where the activation system contained either S9 or isolated microsomes and mutagenicity was determined in the presence of increasing concentrations of theafulvins (0–500 µg/plate). When an S9 activation system was used, theafulvins enhanced the aflatoxin B1-mediated mutagenicity (Figure 2). However, when the S9 activation system was replaced with isolated microsomes, theafulvins provoked a concentration-dependent attenuation of mutagenic activity. Finally, the ability of the hepatic cytosol, supplemented with arachidonic acid, to catalyse the activation of aflatoxin B1 to a mutagenic intermediate(s) was investigated (Figure 3). A positive, but very weak, mutagenic activity was observed.
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The effect of black tea theafulvins on aflatoxin B1 mutagenicity was studied using an approach that makes it possible to discern whether the effect of theafulvins is on the bioactivation of the mycotoxin by hepatic S9 or involves interaction with its reactive intermediate(s). The polyphenols were added either at the beginning of the incubation, i.e. to evaluate its effect on the bioactivation of aflatoxin B1, or following the termination of microsomal metabolism, to establish whether the theafulvins interact with the reactive intermediate(s) of the mycotoxin. When theafulvins were added at the beginning of the incubation, the expected increase in mutagenicity was observed (Figure 4
); if, however, the theafulvins were incorporated into the activation system after termination of microsomal activation, then a decrease was seen at the higher theafulvin concentration (200 µg/plate).
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) by the addition of menadione. Results are presented as means ± SD for triplicate plates. The spontaneous reversion rate of 23 ± 6 has already been subtracted. TFu, theafulvins.Studies were also conducted to assess the effect of black tea theafulvins on the enzyme systems catalysing the detoxification of the major genotoxic metabolite of the mycotoxin, namely aflatoxin B1 8,9-epoxide. When microsomal epoxide hydrolase activity was monitored using benzo[a]pyrene 4,5-epoxide, black tea theafulvins caused a concentrationdependent decrease in activity (Figure 5
). Theafulvins induced a more marked inhibition of cytosolic glutathione S-transferase activity, when monitored using CDNB; when the same enzyme system was monitored using DCNB as the accepting substrate, the effect was relatively modest (Figure 5)
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In order to evaluate whether theafulvins have a direct effect on the bacteria that rendered them more sensitive to aflatoxin B1 mutagenicity, the mutagenic activity of the mycotoxin was determined in bacteria pre-exposed to theafulvins but from which the theafulvins were removed prior to use in the Ames test. Aflatoxin B1 induced a concentration-dependent mutagenic response in both the bacteria pre-exposed to theafulvins and those that were grown in the absence of these polyphenols. However, the mutagenic response was much more pronounced when the bacteria were pre-exposed to the black tea theafulvins (Figure 6
). In a further study we investigated whether the effect of in vitro addition of theafulvins to the activation system was modified by prior exposure of the bacteria to theafulvins. In normal bacteria theafulvins, as expected, potentiated the mutagenic activity of aflatoxin B1, but in bacteria pre-exposed to theafulvins the effect of in vitro addition of theafulvins was much less pronounced (Figure 7).
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Discussion |
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Aflatoxin B1 is a hepatocarcinogenic mycototoxin produced by Aspergillus flavus and Aspergillus parasiticus and is found as a contaminant in many food commodities, including nuts, figs, corn and rice (Wang et al., 1998
). In order to express its carcinogenicity it requires metabolic activation, catalysed by cytochromes P450, to form the electrophilic 8,9-epoxide, which is responsible for its mutagenic activity (Aoyama et al., 1990; Gallagher et al., 1994; Ueng et al., 1995). It is believed that the epoxide is primarily detoxified through conjugation with glutathione, catalysed by the glutathione S-transferases, and hydrolysis, which may be catalysed by the epoxide hydrolases (Neal and Green, 1983; Guengerich et al., 1996). However, experimental evidence indicates that hydrolysis of the 8,9-epoxide by epoxide hydrolase is not an important pathway for its detoxification (Johnson et al., 1997).
In previous studies we have shown that black tea theafulvins, a class of polyphenolic compounds derived from the oxidation of green tea flavanols, possess potent antimutagenic activity against food carcinogens such as polycyclic aromatic hydrocarbons, nitrosamines and heterocyclic amines (Catterall et al., 1998). In the case of aflatoxin B1, however, theafulvins, in contrast, stimulated the mutagenicity of the mycotoxin in a dose-dependent manner. Potentiation of aflatoxin B1 mutagenicity has also been reported for the phenolics butylated hydroxytoluene and butylated hydroxyanisole by Shelef and Chin (1980); these authors, however, did not investigate the underlying mechanisms. Similarly, coumarin increased the mutagenicity of the carcinogen in the presence of human S9 in the Chinese hamster ovary cell/hypoxanthine-guanine phosphoribosyltransferase mutation assay and was attributed to increased cytochrome P450-mediated bioactivation of the mycotoxin (Goeger et al., 1999). Genotoxic synergy has also been reported with many other compounds; for example, paraoxon, a non-genotoxic metabolite of the organophosphorus insecticide parathion, potentiated the mutagenicity of aromatic amines (Wagner et al., 1997).
A number of mechanisms may contribute to the theafulvin-mediated increase in aflatoxin B1 mutagenicity. Theafulvins may: (i) potentiate the activity of the cytochrome P450 enzymes catalysing the activation of the mycotoxin through epoxidation; (ii) impair the metabolism of aflatoxin B1 through deactivation pathways, thus pushing more of the metabolism towards activation; (iii) interact with aflatoxin 8,9-epoxide to form a more mutagenic complex; (iv) facilitate the passage of the epoxide into the bacterial cell or interact with the DNA in such a way as to facilitate covalent binding of the epoxide to DNA.
The most important cytochrome P450 isoforms in the bioactivation of aflatoxin B1 are CYP1A2 and the human CYP3A4 (Aoyama et al., 1990; Crespi et al., 1991; Ueng et al., 1995; Gallagher et al., 1996). Since in the present studies rats were pretreated with Aroclor 1254, a potent inducer of both isoforms of the CYP1A subfamily (Parkinson et al., 1983), it is reasonable to assume that CYP1A2 is the main contributor to the bioactivation of aflatoxin B1. The same enzyme catalyses the bioactivation of heterocyclic amines such as IQ (2-amino-3-methylimidazo[4,5-f]quinoline, and theafulvins have decreased the genotoxicity of this carcinogen, in marked contrast to the potentiation observed with aflatoxin B1. Moreover, theafulvins inhibited the in vitro O-demethylation of methoxyresorufin, a probe for CYP1A2 activity (Catterall et al., 1998). Finally, potentiation of the mutagenic activity of aflatoxin B1 was observed when S9, but not microsomes, functioned as the activation system. Collectively, the above data argue strongly against involvement of stimulation of CYP1A2 activity as a mechanism for the potentiation of aflatoxin B1 mutagenicity in the Ames test by theafulvins and indicate that the presence of the cytosolic fraction is essential for the synergism to occur. Although cytochrome P450 is the principal catalyst of the bioactivation of aflatoxin B1, DNA adducts were generated when the mycotoxin was incubated with cytosolic lipoxygenase (Liu and Massey, 1992), an enzyme that generates peroxyl radicals from arachidonic acid that act as powerful oxidizing agents that can metabolize substrates such as aflatoxin B1 (Kulkarni, 2002). Furthermore, partially purified human lipoxygenase converted aflatoxin B1 to the epoxide in the presence of polyunsaturated fatty acids (Roy and Kulkarni, 1997). Since the synergism between theafulvins and aflatoxin B1 was only noted in the presence of S9, which comprises microsomes and cytosol, but not isolated microsomes, it was considered pertinent to assess the ability of rat liver cytosol from Aroclor 1254-treated rats, in the presence of arachidonic acid, to activate this mycotoxin to mutagenic intermediates in the Ames test. A very weak mutagenic response was observed, barely reaching a doubling of the spontaneous reversion rate, orders of magnitude below that seen in the presence of S9 fortified with NADP. In previous studies no mutagenic response was noted when rat liver cytosol, in the absence of arachidonic acid, was used as the activation system (Woodall et al., 1999). Clearly, this system makes a minimal contribution to the bioactivation of aflatoxin B1; moreover, it should be born in mind that arachidonic acid was not present in the activation system in the experiments where genotoxic synergy was observed.
Aflatoxin B1 may also be hydroxylated by cytochromes P450 to less mutagenic metabolites, such as aflatoxin Q1 and aflatoxin M1 (Raney et al., 1992; Guengerich et al., 1996); in reconstituted systems employing human cytochrome P450 enzymes, the former was metabolized primarily by CYP3A4 and the latter by CYP1A2 (Ueng et al., 1995). The possibility, therefore, exists that theafulvins may inhibit these pathways of aflatoxin B1 metabolism, directing more of the metabolism through the activating epoxidation pathway resulting in potentiation of the mutagenic activity. However, such a mechanism is very unlikely to be responsible for the enhanced mutagenic activity of aflatoxin B1 in the presence of theafulvins, since in Aroclor 1254-treated rats the same cytochrome P450 protein, i.e. CYP1A2, is responsible for both the activation and deactivation pathways.
Aflatoxin B1 may be detoxified by hydrolysis to the dihydrodiol or by conjugation with glutathione, catalysed by the glutathione S-transferases (Guengerich et al., 1998). Theafulvins caused a concentration-dependent decrease in epoxide hydrolase activity, raising the possibility that the underlying mechanism of the interaction is a rise in the levels of aflatoxin B1 8,9-oxide resulting from inhibition of its further metabolism to the inactive dihydrodiol. However, the major xenobiotic-metabolizing epoxide hydrolase is a microsomal enzyme (Arand and Oesch, 2002), and no genotoxic synergism was observed when isolated microsomes served as the activation system. Moreover, epoxide hydrolysis does not appear to be the major route for the detoxification of aflatoxin B1 8,9-oxide, whose major pathway for detoxification is via conjugation with glutathione (Guengerich et al., 1998). In the present study, marked inhibition was evident of the cytosolic glutathione S-transferase activity in the presence of theafulvins, especially when CDNB was used as the substrate. In contrast, only weak inhibition was observed when DCNB was the substrate, suggesting that theafulvins selectively influence only a sub-set of glutathione S-transferase enzymes. Thus, clearly, the stimulation of the mutagenic activity of aflatoxin B1 by theafulvins may be due, at least in part, to impairment of the detoxification of the mutagenic aflatoxin B1 8,9-oxide by glutathione S-transferases. Although no glutathione was added to the activation system, reduced glutathione is present at a high concentration in the cytosol, and 
0.1 µmol is present in the activation system. Such a mechanism would explain the requirement for the presence of the cytosolic fraction for the synergism to become apparent.
An alternative feasible mechanism is that the 8,9-epoxide of aflatoxin B1 may interact with theafulvins to produce a more mutagenic product. Indeed, such a mechanism has been proposed to explain the antimutagenic effect of ellagic acid, another naturally occurring polyphenol, towards aflatoxin B1 in the Ames test (Loarca-Pinã et al., 1996); however, in this case the interaction suppressed the mutagenicity of the mycotoxin, which is in contrast to the effect observed in the current studies with theafulvins. When the theafulvins were added to the activation system after termination of microsomal metabolism, suppression of the mutagenic response was observed and not the potentiation that is evident when the polyphenols are added to a fully functioning activation system. These observations clearly indicate that theafulvins do not interact with the reactive intermediate(s) of aflatoxin B1, or any other microsome-generated metabolite, to form a more mutagenic product. Consequently, such a mechanism may be rejected.
A further mechanism that may account for the experimental findings is that the black tea theafulvins may interact with bacterial DNA in such a way as to facilitate the interaction of the reactive intermediate of aflatoxin B1 and thus enhance the mutagenic response. In support of such a mechanism are the observations that: (i) the mutagenic activity of aflatoxin B1 was far more pronounced in bacteria pretreated with theafulvins but from which it was subsequently washed off and was therefore not present extracellularly, compared with controls; (ii) in vitro addition of theafulvins to the activation system resulted in less potent potentiation of aflatoxin B1 mutagenic activity in theafulvin-treated bacteria compared with untreated bacteria. Clearly, exposure of the bacteria to the theafulvins is sufficient to stimulate the mutagenicity of the mycotoxin and does not necessitate their presence in the incubation mixture. However, if indeed theafulvins facilitate the interaction of aflatoxin B1 8,9-oxide with DNA, it is difficult to rationalize the lack of effect when other mutagens were used (Catterall et al., 1998).
In conclusion, the present studies confirm the genotoxic synergy between aflatoxin B1 and black tea theafulvins and present experimental evidence indicating that this interaction does not occur during the bioactivation of the carcinogen, but may be, at least partly, the consequence of decreased metabolism of aflatoxin B1 8,9-oxide via conjugation with glutathione. The relevance of these data, if any, to the in vivo situation remains to be elucidated.
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Acknowledgments |
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The authors gratefully acknowledge financial support for this study from the European Union under Project PL0653.
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1 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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Received on September 9, 2002; revised on October 30, 2002; accepted on October 31, 2002.
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