- Email: [email protected]
The mutagenicity-enhancing effect of glucose
Mutation Research, 91 (1981) 213-214 Elsevier/North-Holland Biomedical Press
213
THE MUTAGENICITY-ENHANCING EFFECT OF GLUCOSE
N. NASHED Zentrum der Biologischen Chemie, Klinikum der Universitdt Frankfurt, 6000Frankfurt/M 70 (Federal Republic of Germany)
Using a different mutagenicity system in Saccharomyces cerevisiae, we observed, in 1966 [1], a similar glucose-enhancing effect on the induction of mutants as that recently reported by Shirai et al. [2] in S. typhimurium. In our experiments, we observed a doubling of adenine mutants (adl + ad2) in yeast cells treated with lnitrosoimidazolidone-2 when the glucose content of the solid medium was increased f r o m 2 to 8°70. One possible hypothesis to explain this enhancing effect of glucose could be that, as a reducing agent, glucose slowed down the oxidative metabolism of the carcinogen, thus reducing its lethality to such an extent as to permit survival of mutant colonies which would otherwise have died in the absence of added sugar. There is some support for this hypothesis in experiments with rats exposed to dimethylnitrosamine (DMNA) where the carcinogenic action is much more dependent on oxidative metabolism than it is with 1-nitrosoimidazolidone-2. Several reports [3-7] have shown that a prefeeding of rats with a protein-deficient diet composed solely of starch and sucrose, sucrose alone or 50070 sucrose + 50070 glucose (whereby glucose is a major metabolite), before an i.p. dose of D M N A at 50-60 m g / k g , results in less lethality and an enhanced carcinogenesis up to 100°70 a m o n g survivors. Is it possible that the observed enhancement in carcinogenesis is due to the increased survival observed? In other words, glucose seems, if our assumption is correct, to have protected the animals against part of the lethal, but not against the carcinogenic, effect. Could this also be the explanation for the enhanced mutagenic effect cited above in both yeast and bacteria? In view of the important consequences that would have to follow the finding that glucose is involved in enhancing mutagenesis (and probably carcinogenesis, although this requires more direct evidence), it is important that we try to find answers to the above questions. If my hypothesis proves valid, glucose would be expected to enhance mutagenesis (and probably carcinogenesis) only if applied in conjunction with near lethal doses of a mutagen or carcinogen. Because it is not assumed to act by inducing mutations or cell transformations, a glucose saturation given with moderate or low doses of mutagens or carcinogens, would not be 0165 - 7992/81/0000 - 0000/$02.50 © Elsevier/North-Holland Biomedical Press
214 expected to have a n y e n h a n c i n g effect. In these c i r c u m s t a n c e s , no a c t i o n b y c o n t r o l l i n g agencies a g a i n s t glucose w o u l d be called for. F r o m the p o i n t o f view o f m u t a t i o n a n d cancer research, c o n f i r m a t i o n o f the h y p o t h e s i s w o u l d be o f great interest. It w o u l d m e a n t h a t we n o w have a new class o f agents, p r o b a b l y with m a n y c a n d i d a t e s o t h e r t h a n glucose, with a new a n d so far u n e x p e c t e d m e c h a n i s m o f p r o m o t i o n . By reducing r a t h e r t h a n increasing the d a m a g e d o n e b y the a g e n t used, they achieve the s a m e result as classical p r o m o t e r s . T h e y p r o m o t e the rate o f mutagenesis or carcinogenesis b y ' p r o t e c t i n g ' the o r g a n i s m f r o m lethal d a m a g e . I t h e r e f o r e p r o p o s e to call this class o f p r o m o t e r s , for which glucose seems to be the first c a n d i d a t e , ' p r o t e c t i v e p r o m o t e r s ' . REFERENCES 1 Nashed, N., and G. Jabbur, A genetic and functional characterization of adenine mutants induced in yeast by 1-nitrosoimidazolidone-2, Z. Vererbungsl., 98 (1966) 106-110. 2 Shirai, A., et al., Enhancement of the mutagenicities of N-methyl-N'-nitro-N-nitrosoguanidine and Nmethyl-N-nitrosourea by glucose, Mutation Res., 72 (1980) 73-77. 3 Swan, P.F., and A.E.M. McLean, The effect of diet on the toxic and carcinogenic action of dimethylnitrosamine, Biochem. J., 107 (1968) 14-15. 4 McLean, A.E.M., and P.G. Magee, Increased renal carcinogenesis by dimethylnitrosamine in protein deficient rats, Br. J. Exp. Pathol., 51 (1970) 587-590. 5 Hard, G.C., and W.H. Butler, Cellular analysis of renal neoplasia, Induction of renal tumors in dietary conditioned rats by dimethylnitrosamine with an appraisal of morphological characteristics, Cancer Res., 30 (1970) 2796-2805. 6 Hard, G.C., R. Boreland and W.H. Butler, Altered morphology and behaviour of kidney fibroblasts in vitro, following in vivo treatment of rats with a carcinogenic dose of dimethylnitrosamine, Experientia, 27 (1971) 1208-1209. 7 Hard, G.C., Autoradiographic analysis of proliferative activity in rat kidney epithelial and mesenchymal cell populations following a carcinogenic dose of dimethylnitrosamine, Cancer Res., 35 (1975) 3762-3773.
213
THE MUTAGENICITY-ENHANCING EFFECT OF GLUCOSE
N. NASHED Zentrum der Biologischen Chemie, Klinikum der Universitdt Frankfurt, 6000Frankfurt/M 70 (Federal Republic of Germany)
Using a different mutagenicity system in Saccharomyces cerevisiae, we observed, in 1966 [1], a similar glucose-enhancing effect on the induction of mutants as that recently reported by Shirai et al. [2] in S. typhimurium. In our experiments, we observed a doubling of adenine mutants (adl + ad2) in yeast cells treated with lnitrosoimidazolidone-2 when the glucose content of the solid medium was increased f r o m 2 to 8°70. One possible hypothesis to explain this enhancing effect of glucose could be that, as a reducing agent, glucose slowed down the oxidative metabolism of the carcinogen, thus reducing its lethality to such an extent as to permit survival of mutant colonies which would otherwise have died in the absence of added sugar. There is some support for this hypothesis in experiments with rats exposed to dimethylnitrosamine (DMNA) where the carcinogenic action is much more dependent on oxidative metabolism than it is with 1-nitrosoimidazolidone-2. Several reports [3-7] have shown that a prefeeding of rats with a protein-deficient diet composed solely of starch and sucrose, sucrose alone or 50070 sucrose + 50070 glucose (whereby glucose is a major metabolite), before an i.p. dose of D M N A at 50-60 m g / k g , results in less lethality and an enhanced carcinogenesis up to 100°70 a m o n g survivors. Is it possible that the observed enhancement in carcinogenesis is due to the increased survival observed? In other words, glucose seems, if our assumption is correct, to have protected the animals against part of the lethal, but not against the carcinogenic, effect. Could this also be the explanation for the enhanced mutagenic effect cited above in both yeast and bacteria? In view of the important consequences that would have to follow the finding that glucose is involved in enhancing mutagenesis (and probably carcinogenesis, although this requires more direct evidence), it is important that we try to find answers to the above questions. If my hypothesis proves valid, glucose would be expected to enhance mutagenesis (and probably carcinogenesis) only if applied in conjunction with near lethal doses of a mutagen or carcinogen. Because it is not assumed to act by inducing mutations or cell transformations, a glucose saturation given with moderate or low doses of mutagens or carcinogens, would not be 0165 - 7992/81/0000 - 0000/$02.50 © Elsevier/North-Holland Biomedical Press
214 expected to have a n y e n h a n c i n g effect. In these c i r c u m s t a n c e s , no a c t i o n b y c o n t r o l l i n g agencies a g a i n s t glucose w o u l d be called for. F r o m the p o i n t o f view o f m u t a t i o n a n d cancer research, c o n f i r m a t i o n o f the h y p o t h e s i s w o u l d be o f great interest. It w o u l d m e a n t h a t we n o w have a new class o f agents, p r o b a b l y with m a n y c a n d i d a t e s o t h e r t h a n glucose, with a new a n d so far u n e x p e c t e d m e c h a n i s m o f p r o m o t i o n . By reducing r a t h e r t h a n increasing the d a m a g e d o n e b y the a g e n t used, they achieve the s a m e result as classical p r o m o t e r s . T h e y p r o m o t e the rate o f mutagenesis or carcinogenesis b y ' p r o t e c t i n g ' the o r g a n i s m f r o m lethal d a m a g e . I t h e r e f o r e p r o p o s e to call this class o f p r o m o t e r s , for which glucose seems to be the first c a n d i d a t e , ' p r o t e c t i v e p r o m o t e r s ' . REFERENCES 1 Nashed, N., and G. Jabbur, A genetic and functional characterization of adenine mutants induced in yeast by 1-nitrosoimidazolidone-2, Z. Vererbungsl., 98 (1966) 106-110. 2 Shirai, A., et al., Enhancement of the mutagenicities of N-methyl-N'-nitro-N-nitrosoguanidine and Nmethyl-N-nitrosourea by glucose, Mutation Res., 72 (1980) 73-77. 3 Swan, P.F., and A.E.M. McLean, The effect of diet on the toxic and carcinogenic action of dimethylnitrosamine, Biochem. J., 107 (1968) 14-15. 4 McLean, A.E.M., and P.G. Magee, Increased renal carcinogenesis by dimethylnitrosamine in protein deficient rats, Br. J. Exp. Pathol., 51 (1970) 587-590. 5 Hard, G.C., and W.H. Butler, Cellular analysis of renal neoplasia, Induction of renal tumors in dietary conditioned rats by dimethylnitrosamine with an appraisal of morphological characteristics, Cancer Res., 30 (1970) 2796-2805. 6 Hard, G.C., R. Boreland and W.H. Butler, Altered morphology and behaviour of kidney fibroblasts in vitro, following in vivo treatment of rats with a carcinogenic dose of dimethylnitrosamine, Experientia, 27 (1971) 1208-1209. 7 Hard, G.C., Autoradiographic analysis of proliferative activity in rat kidney epithelial and mesenchymal cell populations following a carcinogenic dose of dimethylnitrosamine, Cancer Res., 35 (1975) 3762-3773.