Abstract
Several lines of evidence point to the probable role of abnormal methylation processes in the toxicology of metals and other xenobiotics. The spectrum of toxic effects exhibited by such metals as Ni, As, and Cd, as well as by Zn deficiency, often resemble those seen in animals chronically fed methyl-deficient diets. These metal-associated pathologies include cancer, atherosclerosis, birth defects, neurological disturbances, and pancreatic lesions. In addition, each of the above agents has been shown to alter normal methyl group metabolism in vivo or in vitro. In the present studies, we compared the effects on the enzyme DNA methyltransferase (MTase) of two metal ions: the essential metal Zn and the carcinogen Cd. MTase extracts were obtained from the hepatic nuclei of rats fed a methyl-deficient diet (lacking choline and folate) for 7 and 24 weeks. Control animals were fed the same diet supplemented with each of these vitamins. Zn and Cd both inhibited MTase in the nuclear extracts from both the control and the methyl-deficient rats. The inhibitory activity of Cd was greater than that of Zn regardless of whether the nuclear extracts were from the control or the deficient animals. In addition, the kinetics of Cd inhibition of MTase activity were different in the nuclear extracts from the control and methyl-deficient rats. The results provide evidence that the carcinogenic effects of Cd may be mediated in part through abnormal DNA methylation.
Full Text
The Full Text of this article is available as a PDF (113.6 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Adams R. L. Eukaryotic DNA methyltransferases--structure and function. Bioessays. 1995 Feb;17(2):139–145. doi: 10.1002/bies.950170209. [DOI] [PubMed] [Google Scholar]
- Bestor T. H. Activation of mammalian DNA methyltransferase by cleavage of a Zn binding regulatory domain. EMBO J. 1992 Jul;11(7):2611–2617. doi: 10.1002/j.1460-2075.1992.tb05326.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chou M. W., Mikhailova M. V., Nichols J., Poirier L. A., Warbritton A., Beland F. A. Interactive effects of methyl-deficiency and dietary restriction on liver cell proliferation and telomerase activity in Fischer 344 rats pretreated with aflatoxin B(1). Cancer Lett. 2000 Apr 28;152(1):53–61. doi: 10.1016/s0304-3835(99)00436-x. [DOI] [PubMed] [Google Scholar]
- Fujiwara Y., Watanabe S., Kaji T. Promotion of cultured vascular smooth muscle cell proliferation by low levels of cadmium. Toxicol Lett. 1998 Feb;94(3):175–180. doi: 10.1016/s0378-4274(98)00005-8. [DOI] [PubMed] [Google Scholar]
- Jones P. A., Buckley J. D. The role of DNA methylation in cancer. Adv Cancer Res. 1990;54:1–23. doi: 10.1016/s0065-230x(08)60806-4. [DOI] [PubMed] [Google Scholar]
- Lopatina N. G., Vanyushin B. F., Cronin G. M., Poirier L. A. Elevated expression and altered pattern of activity of DNA methyltransferase in liver tumors of rats fed methyl-deficient diets. Carcinogenesis. 1998 Oct;19(10):1777–1781. doi: 10.1093/carcin/19.10.1777. [DOI] [PubMed] [Google Scholar]
- Poirier L. A. Methyl group deficiency in hepatocarcinogenesis. Drug Metab Rev. 1994;26(1-2):185–199. doi: 10.3109/03602539409029790. [DOI] [PubMed] [Google Scholar]
- Razmiafshari M., Zawia N. H. Utilization of a synthetic peptide as a tool to study the interaction of heavy metals with the zinc finger domain of proteins critical for gene expression in the developing brain. Toxicol Appl Pharmacol. 2000 Jul 1;166(1):1–12. doi: 10.1006/taap.2000.8950. [DOI] [PubMed] [Google Scholar]
- Ross Sharon A., Poirier Lionel. Proceedings of the Trans-HHS Workshop: diet, DNA methylation processes and health. J Nutr. 2002 Aug;132(8 Suppl):2329S–2332S. doi: 10.1093/jn/132.8.2329S. [DOI] [PubMed] [Google Scholar]
- Thiesen H. J., Bach C. Transition metals modulate DNA-protein interactions of SP1 zinc finger domains with its cognate target site. Biochem Biophys Res Commun. 1991 Apr 30;176(2):551–557. doi: 10.1016/s0006-291x(05)80219-0. [DOI] [PubMed] [Google Scholar]
- Vlasova T. I., Demidenko Z. N., Kirnos M. D., Vanyushin B. F. In vitro DNA methylation by wheat nuclear cytosine DNA methyltransferase: effect of phytohormones. Gene. 1995 May 19;157(1-2):279–281. doi: 10.1016/0378-1119(94)00784-p. [DOI] [PubMed] [Google Scholar]
- Waalkes M. P., Goering P. L. Metallothionein and other cadmium-binding proteins: recent developments. Chem Res Toxicol. 1990 Jul-Aug;3(4):281–288. doi: 10.1021/tx00016a001. [DOI] [PubMed] [Google Scholar]
- Waalkes M. P., Wilson M. J., Poirier L. A. Reduced cadmium-induced cytotoxicity in cultured liver cells following 5-azacytidine pretreatment. Toxicol Appl Pharmacol. 1985 Nov;81(2):250–257. doi: 10.1016/0041-008x(85)90161-9. [DOI] [PubMed] [Google Scholar]