Mutagenesis, Vol. 15, No. 3, 207-213,
May 2000
© 2000 UK Environmental Mutagen Society/Oxford University Press
Vanillin (3-methoxy-4-hydroxybenzaldehyde) inhibits mutation induced by hydrogen peroxide, N-methyl-N-nitrosoguanidine and mitomycin C but not 137Cs 
-radiation at the CD59 locus in human–hamster hybrid AL cells
Department of Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523 and 1 R.J. Reynolds Tobacco, Winston-Salem, NC 27102, USA
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We have investigated the ability of the naturally occurring plant essence vanillin (3-methoxy-4-hydroxybenzaldehyde) to inhibit mutation at the CD59 locus on human chromosome 11 by hydrogen peroxide, N-methyl-N-nitrosoguanidine, mitomycin C and 137Cs
-radiation in human–hamster hybrid AL cells. Previous studies using vanillin have suggested that it can inhibit chromosome aberrations induced by hydrogen peroxide and mitomycin C, as well as inhibiting X-ray- and UV-induced mutations at the hprt locus. Other studies with vanillin have shown that it can increase both the toxicity and mutagenicity of ethyl methane sulfonate and increase the induction of sister chromatid exchange by mitomycin C and a variety of other mutagens. The increased sensitivity of the AL assay, which is due in part to its ability to detect both small (single locus) and large (multilocus) genetic damage, allows us to measure the effect of vanillin at low doses of mutagen. Vanillin is shown, in these studies, to inhibit mutation induced by hydrogen peroxide, N-methyl-N-nitrosoguanidine and mitomycin C, as well as to enhance the toxicity of these agents. Vanillin had no effect on either toxicity or mutation induced by 137Cs -radiation. The vanillin-induced potentiation of H2O2 toxicity is shown not to involve inhibition of catalase or glutathione peroxidase. These results show that vanillin is able to inhibit mutation at the CD59 locus and modify toxicity in a mutagen-specific manner. Possible mechanisms to explain the action of vanillin include inhibition of a DNA repair process that leads to the death of potential mutants or enhancement of DNA repair pathways that protect from mutation but create lethal DNA lesions during the repair process. |
Introduction |
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As much as 50–80% of cancer is thought to depend on lifestyle factors, including diet (Doll and Peto, 1981
). Cancer causing and preventing agents, natural and added, are found in foods so that the possibility of preventing cancer by manipulating food antimutagens is an attractive possibility (Wattenberg, 1985; Boone et al., 1990; Ferguson, 1994; Demarini, 1998). We and others have shown that studies of mutagenesis in cultured mammalian cells can help predict carcinogenesis (Waldren et al., 1986; Matsukura et al., 1991; Ritenour et al., 1991; Hei et al., 1992). The rationale for this approach is based upon evidence that mutation plays a vital role in carcinogenesis and the correlation between the ability of an agent to induce mutations in vitro and its carcinogenic potency. Conversely, the ability of a compound to inhibit induced mutation in vitro suggests that it may be an effective anticarcinogen in vivo.
Vanillin (3-methoxy-4-hydroxybenzaldehyde) is a naturally occurring flavoring ingredient that is found in a variety of food products in concentrations ranging up to 20 000 p.p.m. (Fenaroli, 1975). Studies on the ability of vanillin to inhibit agent-induced mutation and clastogenicity in eukaryotic systems have produced mixed results. Vanillin has been shown to reduce cytotoxicity and the yield of hprt– Chinese hamster V79 cells on acute exposure to UV or X-rays and subsequent culture in the presence of vanillin for 7 days (Imanishi et al., 1990). In vivo mutation studies have shown that oral administration of vanillin shortly after ethylnitrosurea (ENU) injection into pregnant mice can significantly decrease recessive spot formation in the pups (Imanishi et al., 1990). Anticlastogenic effects in cell culture have been shown by vanillin post-treatment following acute UV or X-ray treatment (Sasaki et al., 1990a) and post-treatment following exposure to hydrogen peroxide at 37°C for 1 h (Tamai et al., 1992). Other studies have shown that vanillin can act as an anticlastogen in vivo to suppress both X-ray- (Sasaki et al., 1990b) and mitomycin C (MMC)-induced (Inouye et al., 1988) micronucleus formation in mouse bone marrow cells.
Other studies with vanillin have shown results that contradict it eliciting a protective effect in terms of mutagenicity and clastogenicity. Vanillin treatment has been shown to increase ethyl methane sulfonate (EMS)-induced toxicity at the hprt locus in V79 cells (Tamai et al., 1992). Treatment with vanillin, both pre- and post-MMC exposure, has also been shown to increase the frequency of sister chromatid exchange (SCE) in CHO cells (Sasaki et al., 1987a). A similar effect of vanillin in increasing SCE induced by various alkylating agents has also been shown in CHO cells (Sasaki et al., 1987b). Together these results leave the question of the antimutagenic and anticlastogenic capabilities of vanillin unresolved and suggest a mechanism(s) that will produce varying results depending on the cell system and mutagens employed.
Vanillin has also been shown to be anticarcinogenic in several model systems and species. It was shown to decrease the number of small intestinal tumors induced by multiple agents in a rat multiple organ carcinogenesis bioassay (Akagi et al., 1995) and to reduce the number of preneoplastic glutathione S-transferase 
isoenzyme-positive foci in a rat hepatocarcinogenesis model initiated by 2-amino-3-methylimidazo[4,5-f]quinoline (Tsuda et al., 1994).
It has been proposed that vanillin exerts its antimutagenic activity in damaged cells by promoting recombination and rejoining of DNA at homologous sites (Tamai et al., 1992). Although there is no direct evidence for this hypothesis, a finding consistent with it comes from studies in which induction of chromosome aberrations by UV and X-rays was suppressed by vanillin (Imanishi et al., 1990; Keshava et al., 1998). It has also been found to potentiate the UV-induced SOS DNA repair response in Escherichia coli (Ohta et al., 1988). The fact that vanillin is antimutagenic to such a wide variety of mutagens is consistent with it modulating a process(es), such as DNA repair, which is global in terms of its effect on mutation.
It has also been suggested that vanillin may affect mutation through inhibition or induction of metabolizing enzymes. It can, for instance, induce cytosolic glutathione S-transferase activity in rat liver (Aboobaker et al., 1994), inhibit human liver sulfotransferases (Bamforth et al., 1993) and competitively inhibit the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (Morse et al., 1995). Vanillin may also act as an antioxidant (Liu and Mori, 1993), which may explain its ability to reduce damage induced by H2O2 (Tamai et al., 1992). On the other hand, vanillin also has pro-oxidant effects (Liu and Mori, 1993), is a relatively weak superoxide scavenger and does not inhibit lipid peroxidation in mouse liver microsomes (Zhou and Zheng, 1991).
Previous studies showed that vanillin reduced the toxicity of H2O2 in V79 cells, but since the hprt assay was too insensitive to detect H2O2 as a mutagen, even at high, toxic doses, it was not possible to assess the effects of vanillin on induced mutation. However, it did reduce H2O2-induced chromosome aberrations, so that vanillin may in fact protect against H2O2-induced damage (Tamai et al., 1992).
Literally hundreds of in vitro mutation assay systems have been described (Demarini et al., 1989; Cotton, 1993; Ashby et al., 1994). Many of these assays are suitable to measure intragenic mutations, but they seriously underestimate the incidence of large, multilocus mutations (Demarini et al., 1989; Waldren et al., 1979, 1986), which are at least as important in the cancer process as smaller kinds of mutations (Croce and Klein, 1985; Bishop, 1987). The AL assay detects both small and large mutations. It is, for example, at least 100-fold more sensitive to the mutagenic activity of ionizing radiation and other clastogens than the Chinese hamster ovary (CHO) hypoxanthine guanine phosphoribosyl transferase (hprt) assay and a 1000 times more sensitive than the bacterial Ames test. This makes it possible to quantify the activity of small, non-lethal doses of a mutagen like those to which human populations are likely to be exposed. If, for example, mutation can be detected only at large doses of mutagen that kill most of the cells, then it becomes extremely difficult to study the effects of low doses of antimutagen.
We show here that vanillin reduces the yield of S1– mutants in AL cells exposed to H2O2, N-methyl-N-nitrosoguanidine (MNNG) and MMC, but has no effect on mutant induction by 137Cs -radiation. Vanillin enhanced the toxicity of all three chemical agents, while having no effect on 137Cs -radiation-induced cell killing. These are the first studies showing that vanillin can reduce the mutagenicity of all these chemical agents in a mammalian cell system and show that the AL system is effective for screening potential antimutagens. We propose as possible mechanisms that vanillin may inhibit a DNA repair process, such that enhancement of lethality decreases mutant yield by killing cells with potentially mutagenic lesions, or enhance a repair process, such as mismatch repair, that is known to play a role in the initiation of lethal lesions and protect against mutagenic lesions.
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Materials and methods |
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Chemicals
Catalase, glutathione, glutathione peroxidase, glutathione reductase, hydrogen peroxide (30%), mitomycin C, NADPH, MNNG and vanillin were purchased from Sigma (St Louis, MO). All other reagents were of analytical grade.
Tissue culture
The AL human–hamster hybrid cell line was derived more than 35 years ago by fusion of a CHO cell with a human lymphocyte. The characteristics and use of this cell line in mutation assays have been described in detail (Jones et al., 1975; Waldren et al., 1979, 1999; Hei et al., 1992). AL-AH1-9 cells were maintained in Ham's F12 medium containing 4% fetal calf serum and 3% newborn calf serum (Atlanta Biologicals, Norcross, GA), penicillin/streptomycin and 20 mM HEPES buffer, pH 7.4, in a humidified atmosphere of 95% air/5% CO2 at 37°C in tissue culture plates.
Cytotoxicity assays
Cells were grown in tissue culture dishes as described and were harvested by trypsinization. Trypsinized cells were counted and plated out at an appropriate cell density in the presence or absence of 100 µM vanillin. For studies assessing the toxicity of vanillin to AL cells, cells were plated and allowed to attach in the absence of vanillin and then treated with graded concentrations of vanillin continuously. Following a 3 h period for cell attachment, cells were treated with graded concentrations of H2O2, MNNG, MMC or the appropriate solvent control. H2O2 was diluted to the appropriate concentration in medium, as were stock solutions of vanillin, MNNG and MMC, which were dissolved in water, DMSO and 70% ethanol, respectively. Final solvent concentrations were <0.5% (v/v) in all cases. Cells were exposed to H2O2 for 1 h and to MNNG and MMC for 16 h under the same growth conditions as described earlier. After chemical exposure, cells were washed with saline G and growth medium was re-added. For 137Cs -radiation toxicity, trypsinized cells were plated out at appropriate cell densities as above and, following a 3 h attachment/pretreatment period, they were irradiated at a dose rate of 0.93 Gy/min at room temperature in a Mark I irradiator (J.L. Shepherd and Associates, Glendale, CA). Colony formation was assessed 7–10 days later by fixing, staining and counting. The surviving fraction was determined from colony formation by standard procedures.
Mutation assays
Mutation analysis was carried out as described (McGuiness et al., 1995). Briefly, cells were inoculated and treated as in the toxicity experiments and plated out at a density calculated from survival curves to give 2x105 survivors following mutagen exposure. Following exposure to H2O2, MNNG, MMC or 137Cs -radiation cells were subcultured for 10 days for expression of mutations. Following the expression period, treated and control cells were plated out at 2x105 (H2O2 and 137Cs -radiation) or 105 (MNNG and MMC exposure) in 100 mm dishes in Ultra Culture medium (BioWhitaker, Walkersville, MD) supplemented with 1% heat-inactivated fetal bovine serum, antibiotics and 1 mM L-glutamine. Following a 3 h incubation, the population of cells was `challenged' by the addition of 0.3% (v/v) anti-S1 monoclonal antibody and 2% (v/v) of a mixture of 95% rabbit serum (complement) and 5% human serum. The human serum acts to reduce any non-specific toxicity of the complement. The antibody plus complement quantitatively kills wild-type S1-expressing cells, while mutant S1– cells survive. Control plates for survival of each group were plated out in triplicate in the presence and absence of the rabbit/human serum mixture at 300 cells/plate in 6-well plates to measure any killing by complement itself. After 7–10 days, plates were fixed, stained and surviving colonies counted. Mutant fractions were calculated by normalizing the number of mutants/plate to the plating efficiency (McGuiness et al., 1995).
Calculation of mutant fraction
The mutant fractions (Mf) were calculated as previously described (Waldren et al., 1979), Mf = (number of S1– colonies)x(1/plating efficiency of cells exposed to complement without antiserum), expressed for convenience as mutants/105 surviving cells: Mf = S1– mutants/105 survivors.
Enzyme assays
The enzymatic activities of catalase and glutathione peroxidase were measured in the presence and absence of 100 µM vanillin. All enzyme assays were carried out using a Beckman DU-650 Spectrophotometer (Beckman Coulter, Fullerton, CA).
Catalase activity was measured as previously described (Aebi, 1984). Reaction mixtures consisted of 50 mM potassium phosphate, pH 7.0, and H2O2 to give an absorbance between 0.50 and 0.53 versus an appropriate blank. Bovine liver catalase (EC 1.11.1.6) was then added and the absorbance change monitored at 240 nm. A unit of catalase activity is defined as the amount that decomposes 1 µmol H2O2/min.
Glutathione peroxidase activity was measured as previously described (Strauss et al., 1980). Reaction mixtures consisted of 50 mM phosphate buffer, pH 7.0, 1 mM EDTA, 150 mM reduced glutathione, 8.4 mM NADPH, 4.7 or 47 µM H2O2 and non-limiting amounts of glutathione reductase (Strauss et al., 1980). Bovine erythrocyte glutathione peroxidase (EC 1.11.1.9) was then added and the absorbance monitored at 340 nm. A unit of glutathione peroxidase activity is defined as the amount that decomposes 1 nmol NADPH/min.
Statistics
Statistical analysis for significant difference in the slope of mutant induction in the presence or absence of vanillin was performed using the f-test for comparison of slopes (Kleinbaum et al., 1988). Significant differences for mutant induction in the presence or absence of vanillin were determined using a t-test. All statistical analysis was carried out using MiniTab v.10 (Minitab, State College, PA).
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Results |
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Toxicity and mutagenicity of vanillin to AL cells
The dose–response curve for AL cell killing by vanillin is shown in Figure 1
. Vanillin showed no toxicity to AL cells up to a concentration of 100 µM, but was extremely toxic at concentrations above 1 mM. For all subsequent studies vanillin was used at a concentration of 100 µM, a non-toxic dose. Treatment of AL cells with 100 µM vanillin for 16 h had no effect on the number of S1– mutants present in the treated population. The fraction of S1– mutants in control populations was 52.4 ± 17.1 per 105 surviving cells, compared with 50.5 ± 19.4 for cells treated with 100 µM vanillin (Table I).
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Effect of vanillin on the toxicity and mutagenicity of H2O2
The effect of vanillin on the toxicity and mutagenicity of H2O2 to AL cells was measured and the results are shown in Figure 2
. The inclusion of vanillin led to an increase in the toxicity of H2O2, causing an ~3-fold increase in the sensitivity of AL cells to H2O2 as measured by LD50 dose (Table II). This increase in toxicity was accompanied by a decrease in the number of S1– mutants generated by an equal dose of H2O2 in the presence of vanillin. The decrease in mutant yield at both 200 and 400 µM H2O2 was significant when compared with mutant yield in the absence of vanillin (P = 0.007 and 0.001, respectively). Linear regression analyses of dose versus Mf fitted a regression line y = 0.13x + 43 in the absence of vanillin and y = 0.06x + 36 with vanillin. This 54% reduction in the slope of Mf induction in the presence of vanillin was statistically significant (P < 0.001) as determined using the f-test comparison of slopes.
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Effect of vanillin on the toxicity and mutagenicity of MNNG
As shown in Figure 3
, the inclusion of vanillin led to a slight increase in the sensitivity of cells to killing by MNNG, with the LD50 being 10 ng/ml in the absence of vanillin and 8 ng/ml in the presence of vanillin (Table II
). The inclusion of vanillin decreased the Mf at 2 and 10 ng/ml MNNG from 49.3 ± 14.0 to 38.5 ± 8.1 and from 89.7 ± 25.4 to 60.4 ± 13.8 S1– mutants/105 cells, respectively (Figure 3). There was no significant decrease in the Mf at 2 ng/ml MNNG (P = 0.23) and only a marginally significant decrease at 10 ng/ml MNNG (P = 0.089) as determined using a t-test comparison. The data are fitted by a regression line y = 5.8x + 33 in the absence of vanillin and y = 3.3x + 28 with vanillin. This 44% decrease in the slope in the presence of vanillin was significantly different (P < 0.005) when evaluated using an f-test for comparison of slopes. These results show that the presence of vanillin decreased the Mf following MNNG exposure.
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Effect of vanillin on the toxicity and mutagenicity of MMC
The presence of 100 µM vanillin also led to a slight increase in the sensitivity of AL cells to killing by the antineoplastic antibiotic MMC (Figure 4
). The presence of vanillin decreased the LD50 for MMC from 27 to 15 ng/ml (Table II). The magnitude of the increase in killing with respect to vanillin treatment is similar to that for MNNG (~25% decrease in LD50; Table II). Vanillin caused a significant decrease (P = 0.0091) in the Mf induced by MMC at 50 ng/ml, with 180 ± 38 and 132 ± 32 S1– mutants/105 cells being generated in the absence and presence of 100 µM vanillin, respectively (Figure 4).
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Effect of vanillin on the toxicity and mutagenicity of 137Cs
-radiationThe effect of vanillin on the toxicity and mutagenicity of 137Cs
-radiation to AL cells was measured and the results are shown in Figure 5. Vanillin had no effect on 137Cs -radiation-induced cell killing or mutant induction. The mutant induction data are fitted by a regression line y = 27.3x + 117.0 in the absence of vanillin and y = 21.7x + 122.8 with vanillin. There is no significant difference between the slopes of these regression lines using the f-test for comparison.
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Effect of vanillin on the Mf induced by H2O2, MNNG, MMC and 137Cs
-radiation corrected for doseThe effect of vanillin on the fraction of S1– mutants induced by H2O2, MNNG, MMC and 137Cs
-radiation corrected for the potentiation of toxicity caused by vanillin was calculated and the results are shown in Table III. Induced Mf values were calculated by subtracting the number of mutants at a given dose from the number of background mutants. When induced Mf were calculated per LD50 dose, the decrease in induced Mf afforded by vanillin became more pronounced. Mf/LD50 dose was significantly decreased (P < 0.05) as determined by t-test analysis for H2O2, MNNG and MMC at all doses, but not for 137Cs -radiation.
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Effect of vanillin on catalase and glutathione peroxidase enzymatic activity
Catalase and glutathione peroxidase enzymatic activities were not inhibited by the presence of 100 µM vanillin, as shown in Table IV
. These results show that vanillin does not affect the metabolic breakdown of H2O2 in the cell by either catalase or glutathione peroxidase.
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Discussion |
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Previous studies suggested that the plant essence vanillin (3-methoxy-4-hydroxybenzaldehyde) had antimutagenic and anticarcinogenic activity (Imanishi et al., 1990
; Ferguson, 1994; Tsuda et al., 1994; Akagi et al., 1995) against a variety of diverse mutagens/carcinogens. This broad spectrum of activity and its approval as an `additive' in foods make vanillin an interesting candidate for further studies as a possible dietary antimutagen/anticarcinogen. The mechanism by which vanillin exerts an antimutagenic effect has been discussed, but very few conclusive experiments have been carried out to date in mammalian cells. For example, it has been shown to affect DNA repair processes in bacteria (Ohta et al., 1988) and it may effect DNA rejoining in mammalian cells (Imanishi et al., 1990; Tamai et al., 1992).
An explanation that is consistent with the many effects shown by vanillin, relative to methylating and ethylating agent-induced damage, is that vanillin somehow enhances mismatch repair processes. Previous studies on mismatch repair-deficient cells have shown that they are hypermutable and resistant to methylating and ethylating agent-induced toxicity (Branch et al., 1993; de Wind et al., 1995). It has been proposed that mismatch repair processes are responsible for the induction of lethal lesions in DNA through the introduction of strand breaks in the repair of mismatched alkylated bases (Karran and Bignami, 1992). Cells that are deficient in mismatch repair processes are therefore resistant to MNNG-induced toxicity on the one hand, but are hypermutable on the other (Branch et al., 1993; de Wind et al., 1995). Our results, showing an increase in MNNG-induced killing and a decrease in Mf, are consistent with vanillin enhancing mismatch repair. Previous studies have shown similar effects of vanillin in terms of toxicity, with an enhancement of EMS-induced killing concurrent with an increase in mutation at the hprt locus with vanillin treatment (Tamai et al., 1992).
The ability of vanillin to increase cellular sensitivity to H2O2 and MMC as well as decrease the mutant yield is more difficult to resolve by a mechanism involving mismatch repair. MMC-induced DNA damage can include strand breaks, either by incomplete DNA replication (Sognier and Hittleman, 1986) or through reactive oxygen species generated through MMC redox cycling (Tomasz, 1976; Pritsos and Sartorelli, 1986). It is possible that vanillin modulates an excision step that is involved in the repair of oxidative base damage and therefore effects would be expected with both MMC and H2O2. Vanillin had no effect on catalase and glutathione peroxidase activity, which is a potential mechanism for enhancement of the toxicity of both H2O2 (Martins et al., 1992) and MMC. Previous studies have shown that MMC toxicity can be altered by PZ-51 (Gustafson and Pritsos, 1991), a seleno-organic antioxidant that has glutathione peroxidase-like activity (Muller et al., 1984). Thus, the potential for enhancement of MMC toxicity by inhibition of catalase or glutathione peroxidase is well founded.
Another possibility for the antimutagenic effects of vanillin could be through inhibition of post-replication repair (PRR) of DNA. PRR is a process by which DNA replicated from a damaged template is converted into high molecular weight forms. Damage repaired through PRR occurs due to DNA replication gaps across from damaged/modified bases. Previous studies on PRR-deficient cell lines have shown that these cells are hypersensitive to killing by methylating and ethylating agents as well as to MMC, UV (Waldren et al., 1983; Hentosh et al., 1990) and H2O2 (unpublished data). The CHO-UV-1 PRR mutant has also been shown to be hypomutable at the hprt locus when treated with EMS or UV (Stamato et al., 1981; Hentosh et al., 1990). An interaction of vanillin with PRR could explain both the increase in toxicity of as well as the decrease in mutation due to all the chemical agents tested.
The ability of vanillin to inhibit mutation in AL cells induced by various chemical mutagens suggests that vanillin may be promising in terms of chemopreventive action. The fact that vanillin enhances toxicity shows that it is not interfering with metabolism or binding of potential mutagens, as this type of mechanism would lead to a decrease in DNA damage and thus protect against cell killing. The fact that vanillin had no effect on either the toxicity or mutagenicity of 137Cs -radiation in AL cells points to vanillin interacting at the level of base damage. Large, multilocus deletions predominate with 137Cs -radiation in the AL system (McGuiness et al., 1995), so an interaction at the level of individually damaged bases would have little effect on toxicity or mutation. H2O2, MNNG and MMC would all be expected to induce some degree of base damage at the doses used in these studies. Therefore, the results presented here support a role for vanillin interacting with a DNA repair process, such as excision repair, that works at the level of base damage.
The studies presented here are in agreement with some previous studies looking at the interaction of vanillin with DNA damaging agents, but are in conflict with others. The ability of vanillin to enhance toxicity while decreasing mutagenicity leads to the speculation that vanillin is affecting either metabolic or repair processes that lead to an increase in lethal and decrease in mutagenic lesions.
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Acknowledgments |
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This work was supported by US Public Health Service grants CA36447 and CA56392, the CAW/DBV laboratory discretionary fund and a contract from RJR-Nabisco. D.L.G. was supported by NRSA post-doctoral fellowship CA64039.
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Notes |
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2 Present address: Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO 80262, USA
3 To whom correspondence should be addressed. Tel: +1 970 491 0580; Fax:+1 970 491 0623; Email: cwaldren{at}cvmbs.colostate.edu
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Received on September 7, 1999; accepted on December 6, 1999.
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