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Illusions of safety: antimutagens can be mutagens, and anticarcinogens can be carcinogens
Mutation Research 543 (2003) 191–194
Commentary
Illusions of safety: antimutagens can be mutagens, and anticarcinogens can be carcinogens Errol Zeiger∗ Errol Zeiger Consulting, 1501 Lamont Court, Chapel Hill, NC 27517, USA Received 11 December 2002; accepted in revised form 13 December 2002
Many substances reported to be antimutagens or anticarcinogens have, themselves, been shown to be mutagenic or carcinogenic. von Borstal and Higgins [1] have termed this latter category of chemicals, i.e. those that can be both pro- and antimutagenic and carcinogenic, “Janus carcinogens and mutagens” after the ancient Roman god Janus, who is depicted as having one head with two faces, one looking forward and one looking backward. A number of examples of such chemicals have recently been published, including an article in this issue of Mutation Research by Paolini et al. [2] describing the promise and the realities of -carotene administration as an anticarcinogen. This was the first presumptive anticarcinogen to be included in large-scale, clinical intervention trials. These trials were terminated prematurely when it was discovered that the -carotene treatment was associated with an increased cancer incidence rather than the anticipated decrease in incidence [3–5]. In their article, Paolini et al. assemble the publicly available information about the mechanisms of the agonistic and antagonistic genetic and carcinogenic effects of -carotene. As the author’s describe, the carcinogenicity-enhancing effects could have been foreseen because a chemical such as -carotene, with redox capabilities, can act either as a free-radical scavenger or a free-radical producer, based on the chemical concentration, redox ∗ Tel.: +1-919-932-3778; fax: +1-919-942-5346. E-mail address: [email protected] (E. Zeiger).
state of the test system, and the properties of the specific physiologic pathway being investigated. As examples of the phenomenon discussed by Paolini et al. [2], other recent reports have addressed or emphasized the biphasic nature of many active chemicals. Dashwood [6] provided an ‘A–Z’ listing of substances and diets reported to “modulate” the mutagenicity and/or carcinogenicity of heterocyclic amines. The majority of these modulating substances are plant products or extracts. The title and the text of the article addressed primarily “chemoprevention,” and the majority of the listed substances had been reported to lower mutagenic or carcinogenic responses; the implication being that these substances all had protective effects against mutagenesis and carcinogenesis. The author did, however, note that some of these substances or dietary choices were also mutagenic or carcinogenic by themselves, or had both enhancing and preventive effects. Similarly, a compilation of the antimutagenicity literature by Waters et al. [7] showed that a number of chemicals have both antimutagenic and mutagenic effects—the “direction” of the effect seeming to be dependent on the mutagen used and the test system. It is obvious from the literature behind the ‘A-to-Z’ listing [6] that many authors who report on the antimutagenicity of a substance fail to cite, or downplay, articles showing the mutagenicity and/or carcinogenicity of the same substance. It is also obvious from literature searches that the majority of these “protective”
1383-5742/03/$ – see front matter © 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S1383-5742(02)00111-4
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E. Zeiger / Mutation Research 543 (2003) 191–194
substances have not been tested adequately, or tested at all, for mutagenicity or carcinogenicity. An additional concern is that many published reports of the antimutagenicity of a substance have not addressed rigorously test protocol factors that could have reduced the levels of mutated cells, or adequately examined the substance’s potential mutagenicity. In addition to those mentioned by Dashwood [6], there are numerous other reports in the literature of chemicals that have both mutagenic and antimutagenic activities. For example, Fahrig [8] showed that three substances, testosterone, -estradiol, and diethylstilbestrol, were antimutagens and co-recombinogens in yeast in the absence of S9 but became co-mutagenic and anti-recombinogenic in the presence of rat liver S9. Also, vanillin, which was antimutagenic in mice in vivo, was co-mutagenic in yeast in vitro in the absence of S9. An extreme example of the many facets of an apparent antimutagen was reported recently by Kaya et al. [9]. Co-administration of the same molar concentration range of the antioxidant ascorbic acid, which was not mutagenic in the Drosophila wing spot test, but has been reported to be clastogenic in mammalian cells [10,11], reduced the mutagenicity of potassium chromate to the control level, significantly enhanced the mutagenicity of cobalt chloride, but had no effect on the mutagenicity of 4-nitroquinoline-N-oxide. The final example presented here of the need to look beyond the immediate effects in the specific protocol being used is the juxtaposition of two articles in a recent compendium of studies from a conference that was devoted solely to antimutagenesis and anticarcinogenesis [12]. One report concluded that the in vitro protective effect of their test substance, the natural product resveratrol, in tumor cells was mediated through inhibition of the apoptosis induced by the test mutagen hydrogen peroxide [13]. In the following report, the same laboratory concluded that the protective, i.e. anti-proliferative, effect of a different natural product, eupatilin, against a tumor cell line was caused by its ability to induce apoptosis [14]. Interestingly, the “protective” substance, resveratrol, was reported to induce chromosome aberrations, micronuclei, and SCE in vitro [15]. The anti- and pro-apoptosis effects presented in both papers can be assumed to be valid. However, one logical conclusion from the results presented in the two papers is that in-
duction of apoptosis is bad if it is induced by a mutagen but good if induced by a natural product. A more realistic conclusion is that such fragmented information, especially in a volume devoted to antimutagenesis and anticarcinogenesis, can lead to conclusions that do not address accurately the central issue, i.e. the identification of substances that can mitigate the effects of mutagens and carcinogens in humans. The study of antimutagenesis and anticarcinogenesis is not as simple as it appears from many of the publications. It is clear from the multitude of antimutagenicity and anticarcinogenicity studies in the literature that the modulating responses seen are highly dependent on the test system and protocol used and on the interactions among the specific test chemical(s) and the cell or organism’s physiology and stage of the life cycle. When inhibition is seen, it is often dependent on the specific mutagen or carcinogen whose response one is trying to inhibit. Experiments to demonstrate antimutagenesis or anticarcinogenesis must be rigorous, include all the relevant controls, and be sensitive to increases in activity as well as the decreases being sought. They must also show that toxicity is not a component of the response. People are not exposed to single substances in their diets and environment but to mixtures of substances with differing modes of action. It will not be helpful to identify antimutagens for each individual chemical. The data show that suspect antimutagens and anticarcinogens must be tested at a range of concentrations against a range of mutagen and carcinogen concentrations—and in response ranges that will be sensitive to both increases and decreases in activity. Before a substance is labeled as a putative antimutagen or anticarcinogen, it should be tested for mutagenicity or carcinogenicity with the same rigor. As has been noted previously [16], many of the cellular functions or enzyme systems that are inhibited or co-opted by antimutagens and anticarcinogens in the fulfillment of their activities are functions that are necessary for the cell’s or organism’s survival. Despite the possible modulation of the activity of specific carcinogens or mutagens in a narrowly prescribed protocol, interference with these functions and systems will not benefit the organism in the long term. Oxygen radicals and oxidized reaction products can be mutagenic and carcinogenic. Just as the generation and transfer of oxygen radicals, or electrons, is
E. Zeiger / Mutation Research 543 (2003) 191–194
necessary to life, interference with other mechanisms that may interfere with the activity of mutagens and carcinogens, e.g. blockage of specific receptors, or interference with metabolic pathways, could be detrimental to the health of the organism. A substance that scavenges oxygen or other radicals, e.g. -carotene or ascorbic acid, also has the ability to generate or propagate oxygen radicals. Just as the dose makes the poison, it can also be said that the dose distinguishes the poison from the antidote. These biphasic properties of many test substances have led to situations where documented mutagenic chemicals, and others that have not been tested for carcinogenicity, are being recommended for human use as anticarcinogens. The situation is similar to that documented for -carotene by Paolini et al. [2]. The clear conclusion from this evaluation is that the current practice of identifying antimutagens and anticarcinogens by their activities against specific chemicals in specific test systems is not sufficient to sustain a conclusion that the same substance will be similarly active in other systems. The report on -carotene by Paolini et al. [2] provides a model for the types of information that must be gathered before proclaiming a substance to be a potential anticarcinogen and recommending its use. There is an extensive literature on chemicals or other effects that have been reported to have antimutagenic or anticarcinogenic activity, and the possible mechanisms for such activities. It was not the intention of this commentary to survey or catalogue the literature. Its primary purpose was to note and document the observation that many antimutagenic and anticarcinogenic chemicals also possess mutagenic and carcinogenic activities; some of which appear to be the predominant properties of the chemical, and some of which activities are manifest only under restricted test conditions. This commentary was also intended to reinforce the assertion that antimutagenicity and anticarcinogenicity, although beguiling concepts, are not simple and one-sided, and that reports of antimutagenicity and anticarcinogenicity, similar to reports of mutagenicity or carcinogenicity, should be interpreted with caution. The realization and acceptance of the findings that many substances are not inherently mutagens or antimutagens (or carcinogens or anticarcinogens) should help to better define the issues and will aid in
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the design of laboratory experiments and epidemiology studies to determine the health effects of specific chemicals, dietary regimens, or life styles. These demonstrations of the bifunctional nature of many chemicals may also lead to a reduction in the number of publications and claims (and displays in so-called health food stores) regarding the recommend daily dosing with specific “natural” chemicals or plant products as a preventative against the occurrence of cancer. References [1] R.C. von Borstal, J.A. Higgins, Janus carcinogens and mutagens, Mutat. Res. 402 (1998) 321–329. [2] M. Paolini, S.Z. Abdel-Rahman, A. Sapone, G.F. Pedulli, P. Perocco, G. Cantelli-Forti, M.S. Legator, Beta-carotene: a cancer chemopreventive agent or a co-carcinogen? Mutat. Res., this issue. [3] The Alpha-Tocopherol, Beta-Carotene Prevention Study Group: the effect of Vitamin E and beta-carotene on the incidence of lung cancer and other cancers in male smokers, New Engl. J. Med. 330 (1994) 1029–1035. [4] G.S. Omenn, G.E. Goodman, M.D. Thornquist, J. Balmes, M.R. Cullen, A. Glass, J.P. Keogh, J.P. Meyskens Jr., B. Valanis, J.H. Williams Jr., S. Barnhart, M.G. Cherniack, C.A. Brodkin, S. Hammar, Risk factors for lung cancer and for intervention effects in CARET: the beta-carotene and retinol efficacy trial, J. Natl. Cancer Inst. 88 (1996) 1550–1559. [5] G.S. Omenn, G.E. Goodman, M.D. Thornquist, J. Balmes, M.R. Cullen, A. Glass, J.P. Keogh, F.L. Meyskens, B. Valanis, J.H. Williams, S. Barnhart, S. Hammar, Effects of a combination of beta-carotene and Vitamin A on lung cancer and cardiovascular disease, New Engl. J. Med. 234 (1996) 1150–1155. [6] R.H. Dashwood, Modulation of heterocyclic amine-induced mutagenicity and carcinogenicity: an ‘A-to-Z’ guide to chemopreventive agents, promoters, and transgenic models, Mutat. Res. 511 (2002) 89–112. [7] M.D. Waters, H.F. Stack, M.A. Jackson, H.E. Brockman, S. De Flora, Activity profiles of antimutagens: in vitro and in vivo data, Mutat. Res. 350 (1996) 109–129. [8] R. Fahrig, Antimutagenic agents are also co-recombinogenic and can be converted to co-mutagens, Mutat. Res. 350 (1996) 59–67. [9] B. Kaya, A. Creus, A. Velazquez, A. Yanikoglu, R. Marcos, Genotoxicity is modulated by ascorbic acid: studies using the wing spot test in Drosophila, Mutat. Res. 520 (2002) 93–101. [10] H.F. Stich, J. Karim, J. Koropatnick, L. Lo, Mutagenic action of ascorbic acid, Nature 260 (1976) 722–724. [11] S.M. Galloway, R.B. Painter, Vitamin C is positive in the DNA synthesis inhibition and sister-chromatid exchange tests, Mutat. Res. 60 (1979) 321–327. [12] P.H.M. Lohman, J.M. Gentile, G. Gentile, L.R. Ferguson (Eds.), Antimutagenesis/anticarcinogenesis: screening, methods and biomarkers, Mutat. Res. 496 (2001) 228.
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[13] J.-H. Jang, Y.-J. Surh, Protective effects of resveratrol on hydrogen peroxide-induced apoptosis in rat pheochromocytoma (PC12) cells, Mutat. Res. 496 (2001) 181–190. [14] H.-J. Seo, Y.-J. Surh, Eupatilin: a pharmacologically active flavone derived from Artemisia plants, induces apoptosis in human promyelocytic leukemia cells, Mutat. Res. 496 (2001) 191–198.
[15] A. Matsuoka, K. Takeshita, A. Furuta, M. Ozaki, K. Fukuhara, N. Miyata, The 4 -hydroxy group is responsible for the in vitro cytogenetic activity of resveratrol, Mutat. Res. 521 (2002) 29–35. [16] E. Zeiger, Death and antimutagenicity, Mutat. Res. 466 (2000) 125–127.
Commentary
Illusions of safety: antimutagens can be mutagens, and anticarcinogens can be carcinogens Errol Zeiger∗ Errol Zeiger Consulting, 1501 Lamont Court, Chapel Hill, NC 27517, USA Received 11 December 2002; accepted in revised form 13 December 2002
Many substances reported to be antimutagens or anticarcinogens have, themselves, been shown to be mutagenic or carcinogenic. von Borstal and Higgins [1] have termed this latter category of chemicals, i.e. those that can be both pro- and antimutagenic and carcinogenic, “Janus carcinogens and mutagens” after the ancient Roman god Janus, who is depicted as having one head with two faces, one looking forward and one looking backward. A number of examples of such chemicals have recently been published, including an article in this issue of Mutation Research by Paolini et al. [2] describing the promise and the realities of -carotene administration as an anticarcinogen. This was the first presumptive anticarcinogen to be included in large-scale, clinical intervention trials. These trials were terminated prematurely when it was discovered that the -carotene treatment was associated with an increased cancer incidence rather than the anticipated decrease in incidence [3–5]. In their article, Paolini et al. assemble the publicly available information about the mechanisms of the agonistic and antagonistic genetic and carcinogenic effects of -carotene. As the author’s describe, the carcinogenicity-enhancing effects could have been foreseen because a chemical such as -carotene, with redox capabilities, can act either as a free-radical scavenger or a free-radical producer, based on the chemical concentration, redox ∗ Tel.: +1-919-932-3778; fax: +1-919-942-5346. E-mail address: [email protected] (E. Zeiger).
state of the test system, and the properties of the specific physiologic pathway being investigated. As examples of the phenomenon discussed by Paolini et al. [2], other recent reports have addressed or emphasized the biphasic nature of many active chemicals. Dashwood [6] provided an ‘A–Z’ listing of substances and diets reported to “modulate” the mutagenicity and/or carcinogenicity of heterocyclic amines. The majority of these modulating substances are plant products or extracts. The title and the text of the article addressed primarily “chemoprevention,” and the majority of the listed substances had been reported to lower mutagenic or carcinogenic responses; the implication being that these substances all had protective effects against mutagenesis and carcinogenesis. The author did, however, note that some of these substances or dietary choices were also mutagenic or carcinogenic by themselves, or had both enhancing and preventive effects. Similarly, a compilation of the antimutagenicity literature by Waters et al. [7] showed that a number of chemicals have both antimutagenic and mutagenic effects—the “direction” of the effect seeming to be dependent on the mutagen used and the test system. It is obvious from the literature behind the ‘A-to-Z’ listing [6] that many authors who report on the antimutagenicity of a substance fail to cite, or downplay, articles showing the mutagenicity and/or carcinogenicity of the same substance. It is also obvious from literature searches that the majority of these “protective”
1383-5742/03/$ – see front matter © 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S1383-5742(02)00111-4
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E. Zeiger / Mutation Research 543 (2003) 191–194
substances have not been tested adequately, or tested at all, for mutagenicity or carcinogenicity. An additional concern is that many published reports of the antimutagenicity of a substance have not addressed rigorously test protocol factors that could have reduced the levels of mutated cells, or adequately examined the substance’s potential mutagenicity. In addition to those mentioned by Dashwood [6], there are numerous other reports in the literature of chemicals that have both mutagenic and antimutagenic activities. For example, Fahrig [8] showed that three substances, testosterone, -estradiol, and diethylstilbestrol, were antimutagens and co-recombinogens in yeast in the absence of S9 but became co-mutagenic and anti-recombinogenic in the presence of rat liver S9. Also, vanillin, which was antimutagenic in mice in vivo, was co-mutagenic in yeast in vitro in the absence of S9. An extreme example of the many facets of an apparent antimutagen was reported recently by Kaya et al. [9]. Co-administration of the same molar concentration range of the antioxidant ascorbic acid, which was not mutagenic in the Drosophila wing spot test, but has been reported to be clastogenic in mammalian cells [10,11], reduced the mutagenicity of potassium chromate to the control level, significantly enhanced the mutagenicity of cobalt chloride, but had no effect on the mutagenicity of 4-nitroquinoline-N-oxide. The final example presented here of the need to look beyond the immediate effects in the specific protocol being used is the juxtaposition of two articles in a recent compendium of studies from a conference that was devoted solely to antimutagenesis and anticarcinogenesis [12]. One report concluded that the in vitro protective effect of their test substance, the natural product resveratrol, in tumor cells was mediated through inhibition of the apoptosis induced by the test mutagen hydrogen peroxide [13]. In the following report, the same laboratory concluded that the protective, i.e. anti-proliferative, effect of a different natural product, eupatilin, against a tumor cell line was caused by its ability to induce apoptosis [14]. Interestingly, the “protective” substance, resveratrol, was reported to induce chromosome aberrations, micronuclei, and SCE in vitro [15]. The anti- and pro-apoptosis effects presented in both papers can be assumed to be valid. However, one logical conclusion from the results presented in the two papers is that in-
duction of apoptosis is bad if it is induced by a mutagen but good if induced by a natural product. A more realistic conclusion is that such fragmented information, especially in a volume devoted to antimutagenesis and anticarcinogenesis, can lead to conclusions that do not address accurately the central issue, i.e. the identification of substances that can mitigate the effects of mutagens and carcinogens in humans. The study of antimutagenesis and anticarcinogenesis is not as simple as it appears from many of the publications. It is clear from the multitude of antimutagenicity and anticarcinogenicity studies in the literature that the modulating responses seen are highly dependent on the test system and protocol used and on the interactions among the specific test chemical(s) and the cell or organism’s physiology and stage of the life cycle. When inhibition is seen, it is often dependent on the specific mutagen or carcinogen whose response one is trying to inhibit. Experiments to demonstrate antimutagenesis or anticarcinogenesis must be rigorous, include all the relevant controls, and be sensitive to increases in activity as well as the decreases being sought. They must also show that toxicity is not a component of the response. People are not exposed to single substances in their diets and environment but to mixtures of substances with differing modes of action. It will not be helpful to identify antimutagens for each individual chemical. The data show that suspect antimutagens and anticarcinogens must be tested at a range of concentrations against a range of mutagen and carcinogen concentrations—and in response ranges that will be sensitive to both increases and decreases in activity. Before a substance is labeled as a putative antimutagen or anticarcinogen, it should be tested for mutagenicity or carcinogenicity with the same rigor. As has been noted previously [16], many of the cellular functions or enzyme systems that are inhibited or co-opted by antimutagens and anticarcinogens in the fulfillment of their activities are functions that are necessary for the cell’s or organism’s survival. Despite the possible modulation of the activity of specific carcinogens or mutagens in a narrowly prescribed protocol, interference with these functions and systems will not benefit the organism in the long term. Oxygen radicals and oxidized reaction products can be mutagenic and carcinogenic. Just as the generation and transfer of oxygen radicals, or electrons, is
E. Zeiger / Mutation Research 543 (2003) 191–194
necessary to life, interference with other mechanisms that may interfere with the activity of mutagens and carcinogens, e.g. blockage of specific receptors, or interference with metabolic pathways, could be detrimental to the health of the organism. A substance that scavenges oxygen or other radicals, e.g. -carotene or ascorbic acid, also has the ability to generate or propagate oxygen radicals. Just as the dose makes the poison, it can also be said that the dose distinguishes the poison from the antidote. These biphasic properties of many test substances have led to situations where documented mutagenic chemicals, and others that have not been tested for carcinogenicity, are being recommended for human use as anticarcinogens. The situation is similar to that documented for -carotene by Paolini et al. [2]. The clear conclusion from this evaluation is that the current practice of identifying antimutagens and anticarcinogens by their activities against specific chemicals in specific test systems is not sufficient to sustain a conclusion that the same substance will be similarly active in other systems. The report on -carotene by Paolini et al. [2] provides a model for the types of information that must be gathered before proclaiming a substance to be a potential anticarcinogen and recommending its use. There is an extensive literature on chemicals or other effects that have been reported to have antimutagenic or anticarcinogenic activity, and the possible mechanisms for such activities. It was not the intention of this commentary to survey or catalogue the literature. Its primary purpose was to note and document the observation that many antimutagenic and anticarcinogenic chemicals also possess mutagenic and carcinogenic activities; some of which appear to be the predominant properties of the chemical, and some of which activities are manifest only under restricted test conditions. This commentary was also intended to reinforce the assertion that antimutagenicity and anticarcinogenicity, although beguiling concepts, are not simple and one-sided, and that reports of antimutagenicity and anticarcinogenicity, similar to reports of mutagenicity or carcinogenicity, should be interpreted with caution. The realization and acceptance of the findings that many substances are not inherently mutagens or antimutagens (or carcinogens or anticarcinogens) should help to better define the issues and will aid in
193
the design of laboratory experiments and epidemiology studies to determine the health effects of specific chemicals, dietary regimens, or life styles. These demonstrations of the bifunctional nature of many chemicals may also lead to a reduction in the number of publications and claims (and displays in so-called health food stores) regarding the recommend daily dosing with specific “natural” chemicals or plant products as a preventative against the occurrence of cancer. References [1] R.C. von Borstal, J.A. Higgins, Janus carcinogens and mutagens, Mutat. Res. 402 (1998) 321–329. [2] M. Paolini, S.Z. Abdel-Rahman, A. Sapone, G.F. Pedulli, P. Perocco, G. Cantelli-Forti, M.S. Legator, Beta-carotene: a cancer chemopreventive agent or a co-carcinogen? Mutat. Res., this issue. [3] The Alpha-Tocopherol, Beta-Carotene Prevention Study Group: the effect of Vitamin E and beta-carotene on the incidence of lung cancer and other cancers in male smokers, New Engl. J. Med. 330 (1994) 1029–1035. [4] G.S. Omenn, G.E. Goodman, M.D. Thornquist, J. Balmes, M.R. Cullen, A. Glass, J.P. Keogh, J.P. Meyskens Jr., B. Valanis, J.H. Williams Jr., S. Barnhart, M.G. Cherniack, C.A. Brodkin, S. Hammar, Risk factors for lung cancer and for intervention effects in CARET: the beta-carotene and retinol efficacy trial, J. Natl. Cancer Inst. 88 (1996) 1550–1559. [5] G.S. Omenn, G.E. Goodman, M.D. Thornquist, J. Balmes, M.R. Cullen, A. Glass, J.P. Keogh, F.L. Meyskens, B. Valanis, J.H. Williams, S. Barnhart, S. Hammar, Effects of a combination of beta-carotene and Vitamin A on lung cancer and cardiovascular disease, New Engl. J. Med. 234 (1996) 1150–1155. [6] R.H. Dashwood, Modulation of heterocyclic amine-induced mutagenicity and carcinogenicity: an ‘A-to-Z’ guide to chemopreventive agents, promoters, and transgenic models, Mutat. Res. 511 (2002) 89–112. [7] M.D. Waters, H.F. Stack, M.A. Jackson, H.E. Brockman, S. De Flora, Activity profiles of antimutagens: in vitro and in vivo data, Mutat. Res. 350 (1996) 109–129. [8] R. Fahrig, Antimutagenic agents are also co-recombinogenic and can be converted to co-mutagens, Mutat. Res. 350 (1996) 59–67. [9] B. Kaya, A. Creus, A. Velazquez, A. Yanikoglu, R. Marcos, Genotoxicity is modulated by ascorbic acid: studies using the wing spot test in Drosophila, Mutat. Res. 520 (2002) 93–101. [10] H.F. Stich, J. Karim, J. Koropatnick, L. Lo, Mutagenic action of ascorbic acid, Nature 260 (1976) 722–724. [11] S.M. Galloway, R.B. Painter, Vitamin C is positive in the DNA synthesis inhibition and sister-chromatid exchange tests, Mutat. Res. 60 (1979) 321–327. [12] P.H.M. Lohman, J.M. Gentile, G. Gentile, L.R. Ferguson (Eds.), Antimutagenesis/anticarcinogenesis: screening, methods and biomarkers, Mutat. Res. 496 (2001) 228.
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[13] J.-H. Jang, Y.-J. Surh, Protective effects of resveratrol on hydrogen peroxide-induced apoptosis in rat pheochromocytoma (PC12) cells, Mutat. Res. 496 (2001) 181–190. [14] H.-J. Seo, Y.-J. Surh, Eupatilin: a pharmacologically active flavone derived from Artemisia plants, induces apoptosis in human promyelocytic leukemia cells, Mutat. Res. 496 (2001) 191–198.
[15] A. Matsuoka, K. Takeshita, A. Furuta, M. Ozaki, K. Fukuhara, N. Miyata, The 4 -hydroxy group is responsible for the in vitro cytogenetic activity of resveratrol, Mutat. Res. 521 (2002) 29–35. [16] E. Zeiger, Death and antimutagenicity, Mutat. Res. 466 (2000) 125–127.