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Anti-mutagenic agents are also co-recombinogenic and co-mutagenic agents are also anti-recombinogenic
Fundamentaland Molecular Mechanisms of Mutagenesis
ELSEVIER
Mutation‘Research
326 (1995) 245-246
Series: Current Issues in Mutagenesis and Carcinogenesis,
No. 52
Anti-mutagenic agents are also co-recombinogenic and co-mutagenic agents are also anti-recombinogenic Rudolf Fahrig Fraunhofer-Imtitut j?ir Toxikologie und Aerosolforschung, Abteilung Genetik, Nikolai-Fuchs-Str. 1, 30625 Hannouer, Germany
Received 6 October 1994; accepted 14 October 1994
Keywords:
Co-/anti-mutagenicity;
Anti-/co-recombinogenicity;
In contrast to the large number of chemicals which have been tested for their ability to enhance or reduce mutations, only few chemicals have been tested for co-recombinogenic or antirecombinogenic activity. In general, mutagenic substances are also able to induce recombination because induction of both is dependent on DNA damage. In genetic tests measuring only mutations, an anti-mutagenic effect cannot be distinguished from a simple desmutagenic effect (inactivation of mutagens by whatever means) if mutagen and anti-mutagen are given simultaneously. Simultaneous increase in mutations and decrease in recombinations and vice versa, however, is indicative of interference with DNA repair processes. Parallelism of co-/anti-mutagenic and anti/co-recombinogenic effects was observed in experiments using yeast and mice: tumor promoters * were co-recombinogenic and anti-mutagenic. In contrast to this, co-carcinogenic substances had the opposite effect while substances being tumor promoters as well as co-carcinogens were co-recombinogenic as well as co-mutagenic (Fahrig, 1984, 1987a,b, 1992, 1993). In an attempt to explain these contrasting effects, a model has been developed (Fahrig, 1992).
Tumor
promoter;
Co-carcinogen;
Inorganic
arsenic
This model proposes that nonreciprocal recombination, reciprocal recombination and gene mutation are correlated during mitosis, but that they are separate events: (1) Essentially similar DNA lesions have different genetic consequences, i.e., mutation as well as recombination. (2) The induction of mutation and recombination is correlated, that is, blockade of the pathway of mutation induction leads to channeling of DNA lesions into the pathway of recombination induction, and vice versa. Anti-mutagenic/co-recombinogenic effects can be explained by channeling of DNA lesions into pathways that lead to recombinations by blocking those pathways which lead to mutations. Comutagenic/anti-recombinogenic effects can be
* In carcinogenicity tests, a tumor promoter is applied repeatedly after a single subthreshold dose of an initiating carcinogen. If the two agents are administered simultaneously, this is called co-carcinogenicity. A test is positive when higher tumor incidences occur than either agent would produce alone. In contrast to genotoxic carcinogens that are thought to be effective through their mutagenicity, tumor promoters and co-carcinogens are non-mutagenic, or show at the most a borderline effect.
0027-5107/95/$09.50 0 1995 Elsevier Science B.V. All rights reserved SSDZ 0027-5107(94)00170-7
246
R. Fahrig/Mutation
Research 326 119!95) 245-246
explained by channeling of DNA lesions into pathways that lead to mutations by blocking those pathways which lead to recombinations. Substances that are co-recombinogenic as well as co-mutagenic may act by enhancing both recombinogenic and mutagenic (error-prone) repair mechanisms. De la Rosa et al. (1994) just published observations about simultaneous reduction of the recombinogenic and enhancement of the mutagenic effect of ionizing radiation and alkylating agents by arsenic acid in Drosophila. Exactly this effect of inorganic arsenic has been published 10 years before (Fahrig, 1984). The authors neither knew this paper nor the model explaining these and similar other effects of nongenotoxic carcinogens. Consequently, they were not able to establish a connection with the corresponding results in the literature, and consequently, their own results seemed to be of no great use to them. As I presume that there may perhaps exist unpublished results including such contradictory and difficult-to-explain effects of nongenotoxic carcinogens, I would like to ask if there are collegues
keeping back corresponding results considering these effects too contradictory to be published. Please check your data for such results, and please contact me if you have found anything.
References De la Rosa, M.E., J. Magnusson, C. Ramel and R. Nilsson (1994) Modulating influence of inorganic arsenic on the recombinogenic and mutagenic action of ionizing radiation and alkylating agents in Drosophila melanogaster, Mutation Res., 318, 65-71. Fahrig, R. (1984) Genetic mode of action of cocarcinogens and tumor promoters in yeast and mice, Mol. Gen. Genet., 194, 7-14. Fahrig, R. (1987a) Effects of bile acids on the mutagenicity and recombinogenicity of triethylene melamine in yeast strain MPl and D61.M, Arch. Toxicol., 60, 192-197. Fahrig, R. (1987b) Enhancement of carcinogen-induced mutations or recombinations by 120tetradecanoyLphorbol13-acetate in the mammalian spot test, J. Cancer Res. Clin. Oncol., 113, 61-66. Fahrig, R. (1992) Co-recombinogenic effects, Mutation Res., 284, 185-193. Fahrig, R. (1993) Genetic effects of dioxins in the spot test with mice, Environ. Health Perspect., 101, 257-261.
ELSEVIER
Mutation‘Research
326 (1995) 245-246
Series: Current Issues in Mutagenesis and Carcinogenesis,
No. 52
Anti-mutagenic agents are also co-recombinogenic and co-mutagenic agents are also anti-recombinogenic Rudolf Fahrig Fraunhofer-Imtitut j?ir Toxikologie und Aerosolforschung, Abteilung Genetik, Nikolai-Fuchs-Str. 1, 30625 Hannouer, Germany
Received 6 October 1994; accepted 14 October 1994
Keywords:
Co-/anti-mutagenicity;
Anti-/co-recombinogenicity;
In contrast to the large number of chemicals which have been tested for their ability to enhance or reduce mutations, only few chemicals have been tested for co-recombinogenic or antirecombinogenic activity. In general, mutagenic substances are also able to induce recombination because induction of both is dependent on DNA damage. In genetic tests measuring only mutations, an anti-mutagenic effect cannot be distinguished from a simple desmutagenic effect (inactivation of mutagens by whatever means) if mutagen and anti-mutagen are given simultaneously. Simultaneous increase in mutations and decrease in recombinations and vice versa, however, is indicative of interference with DNA repair processes. Parallelism of co-/anti-mutagenic and anti/co-recombinogenic effects was observed in experiments using yeast and mice: tumor promoters * were co-recombinogenic and anti-mutagenic. In contrast to this, co-carcinogenic substances had the opposite effect while substances being tumor promoters as well as co-carcinogens were co-recombinogenic as well as co-mutagenic (Fahrig, 1984, 1987a,b, 1992, 1993). In an attempt to explain these contrasting effects, a model has been developed (Fahrig, 1992).
Tumor
promoter;
Co-carcinogen;
Inorganic
arsenic
This model proposes that nonreciprocal recombination, reciprocal recombination and gene mutation are correlated during mitosis, but that they are separate events: (1) Essentially similar DNA lesions have different genetic consequences, i.e., mutation as well as recombination. (2) The induction of mutation and recombination is correlated, that is, blockade of the pathway of mutation induction leads to channeling of DNA lesions into the pathway of recombination induction, and vice versa. Anti-mutagenic/co-recombinogenic effects can be explained by channeling of DNA lesions into pathways that lead to recombinations by blocking those pathways which lead to mutations. Comutagenic/anti-recombinogenic effects can be
* In carcinogenicity tests, a tumor promoter is applied repeatedly after a single subthreshold dose of an initiating carcinogen. If the two agents are administered simultaneously, this is called co-carcinogenicity. A test is positive when higher tumor incidences occur than either agent would produce alone. In contrast to genotoxic carcinogens that are thought to be effective through their mutagenicity, tumor promoters and co-carcinogens are non-mutagenic, or show at the most a borderline effect.
0027-5107/95/$09.50 0 1995 Elsevier Science B.V. All rights reserved SSDZ 0027-5107(94)00170-7
246
R. Fahrig/Mutation
Research 326 119!95) 245-246
explained by channeling of DNA lesions into pathways that lead to mutations by blocking those pathways which lead to recombinations. Substances that are co-recombinogenic as well as co-mutagenic may act by enhancing both recombinogenic and mutagenic (error-prone) repair mechanisms. De la Rosa et al. (1994) just published observations about simultaneous reduction of the recombinogenic and enhancement of the mutagenic effect of ionizing radiation and alkylating agents by arsenic acid in Drosophila. Exactly this effect of inorganic arsenic has been published 10 years before (Fahrig, 1984). The authors neither knew this paper nor the model explaining these and similar other effects of nongenotoxic carcinogens. Consequently, they were not able to establish a connection with the corresponding results in the literature, and consequently, their own results seemed to be of no great use to them. As I presume that there may perhaps exist unpublished results including such contradictory and difficult-to-explain effects of nongenotoxic carcinogens, I would like to ask if there are collegues
keeping back corresponding results considering these effects too contradictory to be published. Please check your data for such results, and please contact me if you have found anything.
References De la Rosa, M.E., J. Magnusson, C. Ramel and R. Nilsson (1994) Modulating influence of inorganic arsenic on the recombinogenic and mutagenic action of ionizing radiation and alkylating agents in Drosophila melanogaster, Mutation Res., 318, 65-71. Fahrig, R. (1984) Genetic mode of action of cocarcinogens and tumor promoters in yeast and mice, Mol. Gen. Genet., 194, 7-14. Fahrig, R. (1987a) Effects of bile acids on the mutagenicity and recombinogenicity of triethylene melamine in yeast strain MPl and D61.M, Arch. Toxicol., 60, 192-197. Fahrig, R. (1987b) Enhancement of carcinogen-induced mutations or recombinations by 120tetradecanoyLphorbol13-acetate in the mammalian spot test, J. Cancer Res. Clin. Oncol., 113, 61-66. Fahrig, R. (1992) Co-recombinogenic effects, Mutation Res., 284, 185-193. Fahrig, R. (1993) Genetic effects of dioxins in the spot test with mice, Environ. Health Perspect., 101, 257-261.