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Mutagenesis Advance Access originally published online on December 14, 2006
Mutagenesis 2007 22(1):43-47; doi:10.1093/mutage/gel057
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© The Author 2006. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Mutagenicity of UV-irradiated maltol in Salmonella typhimurium

Mie Watanabe-Akanuma1,*, Yohei Inaba2 and Toshihiro Ohta2

1 Kureha Corporation Biomedical Research Laboratories 3-26-2, Hyakunin-cho, Shinjuku, Tokyo 169-8503, Japan 2 School of Life Science, Tokyo University of Pharmacy and Life Science 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan

We investigated the photomutagenicity of maltol (3-hydroxy-2-methyl-4H-pyran-4-one) in bacterial cells. Maltol has a caramel-butterscotch odour and is used as a food additive to impart flavour to bread and cakes. Unirradiated maltol was not mutagenic up to 5 mg/plate in the Ames test. When maltol was irradiated with either UVA (a black light, 320–400 nm, 230 µW/cm2) for 5–30 min or UVC (a germicidal lamp, 610 µW/cm2) for 3 min in sodium phosphate buffer (pH 7.4) prior to the exposure of bacterial cells, it was mutagenic to Salmonella typhimurium TA100, TA104 and TA97. Mutagenic activation of maltol by UVA-irradiation was more evident in neutral and alkaline conditions (pH 7.0–9.0) than in acidic conditions. On the other hand, photomutagenicity was not observed when maltol was irradiated with UVA in 100 mM NaCl solution or water. The mutagenic photoproduct was stable for at least 60 min after UVA-irradiation. However, addition of thiol compounds (cysteine or glutathione) to the UVA-irradiated maltol diminished the mutagenicity. Mutational spectrum analysis revealed that the predominant base-substitutions induced were G:C->T:A transversions and G:C->A:T transitions. An increase of 8-hydroxydeoxyguanosine formation in salmon sperm DNA exposed to maltol and UVA in vitro was detected by HPLC-ECD, but it was too small to explain the photomutagenicity. We are considering the formation of DNA adducts as the photomutagenic mechanism.


   Introduction
Top
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Kojic acid (5-hydroxy-2-hydroxymethyl-4H-pyran-4-one), which had been used as a food additive and in cosmetics, was withdrawn from the list of existing food additives in Japan in 2003, because the possibility of involvement of genotoxicity of kojic acid in mouse hepatoma development could not be excluded. Since there were contradictory reports on the mutagenicity of kojic acid (1Go), collaborative studies had started using samples with different purity (2Go). We investigated the contribution of possible photomutagenicity of kojic acid with Salmonella reverse mutation assay and found no enhancement of mutagenicity of kojic acid by UVA-irradiation (M. Watanabe-Akanuma, unpublished data). On the other hand, we unexpectedly found photomutagenic property of maltol (3-hydroxy-2-methyl-4H-pyran-4-one), a structurally similar compound. Maltol is a naturally occurring compound found in bark of larch trees, chicory oils and roasted malt. It has a caramel-butterscotch odour and is used as a flavouring to impart ‘freshly baked’ odour and flavour to bread and cakes. The photomutagenic property of maltol, however, would not be serious in respect to human health risk, since a small amount of maltol is used in food products as a flavour enhancer. Rather we interested in the photomutagenic mechanism involved in maltol but not in kojic acid.

UV irradiation can generate photoproducts that cause mutations via different types of mechanisms. One is the generation of short-lived products such as reactive oxygen species or the molecules in their short-lived excited state that react directly with the DNA (3Go–7Go). Another is the formation of more stable photoproducts upon irradiation. Photomutagenicity of maltol was the latter case. Some aromatic and heterocyclic amines such as 2-aminofluorene, 2-acetylaminofluorene, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-3,4-dimethylimidazo-[4,5-f]quinoline (MelQ) are reported to form highly stable direct-acting mutagenic photoproducts by irradiation with near-UV light (8Go). 7,12-Dimethylbenz[a]anthracene, a polycyclic aromatic hydrocarbon compound, showed direct-acting mutagenicity following fluorescent lamp illumination (9Go). Some N-nitroso compounds, such as N-nitrosopiperidine, N-nitrosodimethylamine and N-nitrosopyrrolidine, are another class of photomutagens that were converted to direct-acting mutagens by UVA-irradiation (10Go–13Go). However, the mechanisms leading to photomutagenicity as well as the identification of mutagenic photoproducts have not always been elucidated. Since the photomutagenic property of pyrone compounds has not been reported, we investigated the mechanisms of photoactivation of maltol in this study.


   Materials and methods
Top
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Chemicals, bacterial strains and mutation test
Maltol (>99%) was purchased from Wako Pure Chemical Industries, (Tokyo) and dissolved in dimethyl sulfoxide (DMSO) at 100 mg/ml. L-cysteine and glutathione (reduced form) were purchased from Wako Pure Chemical Ind. and Sigma-Aldrich, MO, USA, respectively. We used Salmonella typhimurium strains TA100 [hisG46, uvrB, rfa/pKM101], TA98 [hisD3052, uvrB, rfa/pKM101], TA97 [hisD6610, uvrB, rfa/pKM101] and TA104 [hisG428, uvrB, rfa/pKM101] (14Go,15Go) for the reverse mutation assays and cultured them in Oxoid nutrient medium at 37°C. Minimal glucose agar plates consisted of Vogel–Bonner E medium supplemented with 2% glucose and 1.5% agar (14Go). Top agar (0.6% agar and 0.5% NaCl) contained 0.05 mM D-biotin and 0.05 mM L-histidine. We treated 0.1 ml bacterial culture in a test tube with the UVA (or UVC)-irradiated maltol solution (0.5 ml) at 37°C for 20 min. We plated the mixture with 2 ml molten top agar, incubated the plates for 2 days at 37°C and then counted the number of His+ revertant colonies. In another experiment, we added 50 µl cysteine or glutathione solution (dissolved in phosphate buffer, pH 7.4) to the UVA-irradiated maltol solution and incubated it at 37°C for 5 min prior to exposure to bacterial cells. All experiments were conducted in duplicate, the control in triplicate. We judged as positive a doubling of the control value together with a dose-related response.

We used Escherichia coli strains WP3101P–WP3106P (16Go) to determine the mutational spectrum. These strains are F' plasmid-carrying derivatives of strain WP2000P [uvrA155, trpE65, {Delta}(lac-pro)/pKM101] and exhibit a Lac–, Trp– phenotype. Each of the six F' plasmids (lac–, lacZ –, proAB+) has a unique lacZ mutation at the codon for Glu-461 (17Go). The mutations necessary for Lac+ reversion are A:T->C:G for WP3101P, G:C->A:T for WP3102P, G:C->C:G for WP3103P, G:C->T:A for WP3104P, A:T->T:A for WP3105P and A:T->G:C for WP3106P. The MGT medium, ML agar plates, NBT-top agar and the assay method have been described previously (16Go,18Go). We conducted the experiments in triplicate for each dose and used five plates for the control. The data presented in the figures are the means of two experiments.

UVA and UVC irradiation
We added maltol (1–15 µl of 100 mg/ml solution dissolved in DMSO) into 0.5 ml 100 mM sodium phosphate buffer (pH 7.4) in each well of a 24-well multiplate and then irradiated it with UVA for 5–30 min or UVC for 1–3 min at room temperature. In some experiments, we used sodium phosphate buffer with a different pH, 10 mM Tris–HCl buffer, 100 mM NaCl or 10 mM NaHCO3. We used a black-light fluorescent lamp (National Black Light Blue, FL15BL-B, 15W, Matsushita Electric Industrial, Japan) that emitted wavelengths of 300–400 nm as the UVA source. To filter out UVB wavelengths below 320 nm, a 5 mm thick soft glass plate was used (10Go–12Go,19Go). The solution in a lidded 24-well multiplate was irradiated with UVA from a distance of 20 cm at 230 µW/cm2 (UVX Radiometer, Model UVX-36, Ultra-Violet Products, Upland, CA, USA). On the other hand, we used a germicidal lamp (Toshiba, GL-15) as the UVC source and irradiated solutions on a multiplate without a lid at 610 µW/cm2 (UVX Radiometer, Model UVX-25).

8-OHdG Assay
We dissolved maltol in 10 mM Na-phosphate buffer at 10 mg/ml. We dissolved salmon sperm DNA (Wako Pure Chemical) in TE buffer at 5 mg/ml and dialysed it against 10 mM Na-phosphate buffer (pH 7.4). We mixed DNA (0.5 mg) and maltol (0.06, 0.13, 0.25, 0.5 and 1.0 mg) into 0.25 ml sodium phosphate buffer in each well of a 24-well multiplate (final concentrations of maltol were 0.25, 0.5, 1, 2 and 4 mg/ml), irradiated the mixture with UVA for 20 min, and then dialysed the reaction mixture against water. N-nitrosopyrrolidine (Sigma-Aldrich) dissolved in sodium phosphate buffer was used as a positive control (12Go, 20Go). We treated the dialysed DNA with Nuclease P1 (5 unit, Seikagaku, Tokyo) in sodium acetate buffer (20 mM, pH 4.8) at 37°C for 2 h, and then by bacterial alkaline phosphatase (1 unit, Takara Bio Inc., Shiga, Japan) in Tris–HCl buffer (100 mM, pH 8.0) at 37°C for an additional 2 h (20Go). We then removed the enzymes by ultrafiltration (14 000 g, 10 min) with Microcon YM-30 (Millipore, USA), added 1 µl 500 mM EDTA (pH 8.0) to the filtered samples and kept the mixture at –20°C. We measured the amount of deoxyguanosine (dG) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) using a high-performance liquid chromatography (HPLC) system (Tosoh, Japan). The system was composed of two pumps (CCPM-II), a degasser (SD-8020), an autosampler (AS-8020), a column oven (CO-8020), a reverse-phase column (Hyderosphere C18, 5 µm, 150 x 4.6 mm ID, YMC, Japan), a UV detector (UV-8020) and an electrochemical detector (ECD, EC-8020). We used Tosoh HPLC Multi Station software (LC-8020) for data acquisition. A 25 µl of sample was injected into the HPLC system. 8-OHdG and dG were eluted at a flow rate of 1 ml/min. We used two solvents for gradient elution—solvent A (2% acetonitorile in 10 mM phosphate buffer and 1 mM EDTA, pH 7.0) and solvent B (8% acetonitrile in the same buffer). The elution conditions were as follows: 0–5 min 0% solvent B; 5–20 min, 0–100% solvent B; 20–25 min 100% solvent B isocractic; 25–30 min 100–0% solvent B. The column temperature was maintained at 35°C. 8-OHdG was detected with the ECD equipped with glassy carbon working electrode operated at +500 mV versus a Ag/AgCl reference electrode. dG was measured by UV absorption at 254 nm. Data were expressed as 8-OHdG/105 dG (nM).


   Results
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 Introduction
 Materials and methods
 Results
Discussion
 References
 
Photomutagenic property
When maltol was irradiated with UVA for 5–30 min in 100 mM sodium phosphate buffer (pH 7.4) prior to incubation with bacterial cells (TA100), it was mutagenic in proportion to the irradiation time (Figure 1), while non-irradiated maltol was not mutagenic. UVC-irradiation also effectively activated maltol (Figure 1). At pH 7.4, 10 mM sodium phosphate was more conductive than 100 mM to photoactivation (Table I). Photoactivation was pH dependent. In 10 mM sodium phosphate buffer, photomutagenicity decreased with pH starting at pH 6.0. Photomutagenicity was observed in 10 mM Tris–HCl buffer (pH 7.5 and 8.3) and 10 mM NaHCO3 (pH 8.9) indicating that photoactivation did not require phosphate anion. UVA-irradiation did not activate maltol in 100 mM NaCl or in water (Table I). UVC, however, did activate maltol in 100 mM NaCl, suggesting photoactivation of maltol required greater energy in NaCl solution than in other buffer solutions.


Figure 1
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  		Fig. 1. Photomutagenicity of UV-irradiated maltol in S. typhimurium TA100. Maltol was irradiated in sodium phosphate buffer (100 mM, pH 7.4) with UVA for 5 (open triangle) or 30 min (open circle), or UVC for 3 min (filled diamond) prior to addition of bacterial cells. Unirradiated maltol (filled circle) showed no mutagenicity. Data are the mean of two experiments. The vertical bars indicate the range in the two experiments.

 


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  		Table I. Effect of pH on photoactivation of maltol

 
Mutational specificity and 8-OHdG
When UVA-irradiated maltol was assayed with 4 different tester strains, it was mutagenic in TA100 (14 times the control value at 1 mg/plate), less in TA97 and TA104 (~5 times the control value at 1 mg/plate), and almost non-mutagenic to TA98 (Figure 2). Therefore, UVA-irradiated maltol induced both –1 frameshift and base-substitution mutations. To investigate the spectrum of the base-substitutions we conducted a Lac+ reversion assay using E. coli strains WP3101P–WP3106P. UVA-irradiated maltol induced predominantly G:C->T:A transversions (15 times the control value) and G:C->A:T transitions (9 times the control) as shown in Figure 3. Other types of base pair substitutions were not detected. Since G:C->T:A transversions, which are typically caused by oxidative DNA damage (21Go), predominated, we investigated the contribution of 8-hydroxyguanine to the photomutagenicity of maltol. The ratio of 8-OHdG/dG in a UVA-irradiated mixture of DNA and maltol in an in vitro experiment was ~1.7 times that of the corresponding non-irradiated control (Figure 4). The results indicated that the contribution of 8-OHdG to the photomutagenicity of maltol was very small.


Figure 2
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  		Fig. 2. Photomutagenicity of UVA-irradiated maltol in S. typhimurium strains. Maltol was irradiated in sodium phosphate buffer (100 mM, pH 7.4) with UVA for 30 min and then assayed with TA100 (filled circle), TA104 (open circle), TA97 (filled triangle) and TA98 (open triangle). Data are the mean of two experiments. The vertical bars indicate the range in the two experiments.

 


Figure 3
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  		Fig. 3. Base substitutions induced by UVA-irradiated maltol in E. coli strains WP3101P-WP3106P. Maltol was irradiated in sodium phosphate buffer (100 mM, pH 7.4) with UVA for 30 min. Open bar, spontaneous Lac+ revertants/plate; grey bar, Lac+ revertants/plate induced by UVA-irradiated maltol at 1 mg/well. Data are the mean of two experiments. The vertical bars indicate the range in the two experiments.

 


Figure 4
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  		Fig. 4. 8-OHdG formation in DNA exposed to maltol and UVA. A mixture of DNA and maltol (0, 0.25, 0.5, 1, 2 and 4 mg/ml) in sodium phosphate buffer (10 mM, pH 7.4) was irradiated with UVA for 30 min. NPR (2 mg/ml) was used as a positive control. Open bar, DNA and maltol (or NPR) without UVA; grey bar, DNA and maltol (or NPR) with UVA. Data are the mean of two experiments. The vertical bars indicate the range in the two experiments.

 
Stability of photoactivated maltol and inactivation by cysteine
The photomutagenic product(s) derived from UVA-irradiated maltol was considerably stable in a pH 7.4 sodium phosphate buffer. Maltol solution kept at room temperature in the dark after UVA-irradiation was equally mutagenic to TA100 after 30 min, and about 80% mutagenic activity remained at 60 min (Figure 5). Similar results were obtained in TA97 (data not shown). On the other hand, the addition of thiol compounds diminished the mutagenicity. At 200 µg cysteine/well (dissolved in sodium phosphate buffer, pH 7.4), the number of induced revertants of TA100 was reduced by 80% (Figure 6). Similar results were observed with glutathione (data not shown).


Figure 5
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  		Fig. 5. Stability of mutagenic products in UVA-irradiated maltol. Maltol at indicated doses was irradiated in sodium phosphate buffer (100 mM, pH 7.4) with UVA for 10, 20 or 30 min. Immediately after (filled circle), or 30 (open triangle) and 60 min (open square) after the irradiation, mutagenicity was assayed with TA100. Representative data obtained from UVA-irradiation for 20 min was presented.

 


Figure 6
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  		Fig. 6. Inhibitory effect of cysteine on photomutagenicity of maltol. Maltol at 1 mg/well was irradiated in sodium phosphate buffer (100 mM, pH 7.4) with UVA for 20 min. Cysteine (dissolved in the same buffer) was added and the mixture was kept at room temperature for 5 min prior to addition to bacteria. Data are the mean of two experiments. The vertical bars indicate the range in the two experiments.

 

   Discussion
Top
 Introduction
 Materials and methods
 Results
 Discussion
References
 
We previously reported that thiabendazole (TBZ), a post-harvest fungicide, shows potent mutagenicity following UVA irradiation, probably by adduct formation, in E. coli WP2uvrA/pKM101 and the predominant mutations were G:C->A:T transitions and A:T->T:A transversions (7Go). The photomutagenic product was unstable, because photomutagenicity was observed when cells were irradiated by UVA in the presence of TBZ, but pre-irradiated TBZ was not mutagenic (22Go). Unlike the TBZ photoproducts, the maltol photoproducts were stable and had mutagenic activity at least 60 min after irradiation. The product, however, were relatively unstable (or less formed) under acidic conditions compared with neutral and alkaline conditions (Table I) and quickly reacted with thiol compounds, resulting in loss of mutagenicity (Figure 6). The formation of mutagenic phosphate esters by UVA-irradiated N-nitrosopypiperidine and N-nitrosopyrrolidine has been reported (10Go,23Go), but that does not appear to be a mechanism involved with maltol, however, because photomutagenicity was observed with UVA-irradiation in Tris–HCl buffer and NaHCO3 solution (Table I). Analysis of the mutagenic specificity of UVA-irradiated maltol revealed that the predominant base-substitutions induced were G:C->T:A transversions, but formation of 8-OHdG was not likely to be an important lesion. In addition, –1 frameshift mutations (TA97) were efficiently induced. Photomutagenicity of maltol was not detected in excision repair-proficient (uvrB+) strains TA102 and TA92 (data not shown), suggesting that the DNA damage generated was repaired by the excision repair system. Although the photomutagenic mechanism of UVA-irradiated maltol has not been clarified, we suspect that DNA bulky adduct formation may be involved.

It has been reported that 5-hyroxymaltol, a glucose pyrolysate, is almost as mutagenic to TA100 as to E. coli WP2uvrA/pKM101 (24Go). UVA-irradiated maltol, on the other hand, was barely mutagenic to WP2uvrA/pKM101 (data not shown). We are trying to isolate the mutagenic compound by HPLC. In our preliminary analysis of an active HPLC fraction by LC-TOF/MS, we could not find a signal corresponding to 5-hydroxymaltol (m/z 142) among several signals detected (M. Watanabe-Akanuma, unpublished data). Further investigation is needed to identify the mutagenic compound(s) and clarify the photomutagenic mechanism.

On the other hand, there were contradictory reports on the bacterial mutagenicity of maltol itself. It was reported to be a weak mutagen to S. typhimurium TA100 (25Go), but others obtained negative results in the Ames/Salmonella test with and without S9mix (26Go). In our present assay, maltol without UV-irradiation was not mutagenic to Salmonella strains TA100, TA98, TA97 and TA104. Mutagenic photoproduct of maltol might explain the discrepancy.


   Acknowledgments
 
We thank Dr Miriam Bloom for her critical reading of the manuscript. This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan (18602003).


   Notes
 
*To whom correspondence should be addressed. Tel: +81 3 3362 7420; Fax: +81 3 3362 8522; Email: akanuma{at}kureha.co.jp


   References
Top
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received on July 18, 2006; revised on September 12, 2006; accepted on October 26, 2006.


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