Zinc and Zinc Related Enzymes in Precancerous and Cancerous Tissue in the Colon of Dimethyl Hydrazine Treated Rats

  • Christudoss, Pamela (Department of Clinical Biochemistry, Christian Medical College) ;
  • Selvakumar, R. (Department of Clinical Biochemistry, Christian Medical College) ;
  • Pulimood, Anna B. (Department of Gi Sciences, Christian Medical College) ;
  • Fleming, Jude Joseph (Department of Clinical Biochemistry, Christian Medical College) ;
  • Mathew, George (Department of General Surgery, Christian Medical College)
  • Published : 2012.02.29


Trace element zinc deficiency or excess is implicated in the development or progression of some cancers. The exact role of zinc in the etiology of colon cancer is unclear. To cast light on this question, an experimental model of colon carcinogenesis was applied here. Six week old rats were given sub cutaneous injections of DMH (30 mg/kg body weight) twice a week for three months and sacrificed after 4 months (precancer model) and 6 months (cancer model). Plasma zinc levels showed a significant decrease (p<0.05) at 4 months and a greater significant decrease at 6 months (p<0.01) as compared with controls. In the large intestine there was a significant decrease in tissue zinc levels (p<0.005) and in CuZnSOD, and alkaline phosphatase activity (p<0.05) in the pre-cancerous model and a greater significant decrease in tissue zinc (p<0.0001), and in CuZnSOD and alkaline phosphatase activity (p<0.001), in the carcinoma model. The tissue zinc levels showed a significant decrease in the small intestine and stomach (p<0.005) and in liver (p<0.05) in the cancer model. 87% of the rats in the precancer group and 92% rats in the cancer group showed histological evidence of precancerous lesions and carcinomas respectively in the colon mucosa. This study suggests that the decrease in plasma zinc, tissue zinc and activity of zinc related enzymes are associated with the development of preneoplastic lesions and these biochemical parameters further decrease with progression to carcinoma in the colon.


Colon cancer;zinc;DMH;CuZnSOD;alkaline phosphatase;precancerous


  1. Anisimov P, Popovich IG (1997). Melatonin and colon carcinogensis : inhibitory effect of melatonin on development of intestinal tumors induced by 1,2-dimethyl hydrazine in rats. Carcinogenesis, 18, 1549-53.
  2. Berg JM (1990). Zinc finger domains: hypothesis and current knowledge. Ann Rev Biophys Chem, 19, 405-21
  3. Bird RP (1995). Role of aberrant crypt foci in understanding the pathogenesis of colon cancer. Cancer Letters, 93, 55-71.
  4. Brown DA, Chattel KW, Chan AY, Knight B (1980). Cytosolic level and distribution of copper and zinc in pretumors from diethyl nitrosamine-exposed mice and in non-cancerous tissue from cancer patients. Chem Biol Interact, 32, 13-27
  5. Cameron L, Hardman H (1997). The nonfermentable dietary fiber lignin alters putative colon cancer risk factors but does not protect against DMH induced colon cancer in rats. Nutr Cancer, 28, 170-6.
  6. Choo Y, Klug A (1997). Physical basis of a protein -DNA recognition code. Curr Opinion Struct Boil, 7, 117-25.
  7. Corpet DE, Tache S (2002). Most effective colon cancer chemo preventive agents in rats: a systematic review of aberrant crypt foci and tumor data, ranked by potency. Nutr and Cancer, 43,1-21.
  8. Davis C, Feng Y (1999). Dietary copper, manganese and iron affect the formation of aberrant crypts in colon of rats administered 3,2"dimethyl -4-aminobiphenyl. J Nutr, 129, 1060-7.
  9. Dionisi D, Galeotti T, Terranove T, Azzi A(1975). Superoxide radicals and hydrogen peroxide formation in mitochondria from normal and neoplastic tissues. Biochim Biophys Acta, 403, 292-300.
  10. Dorai B, Bachhawat BK (1997). Purification and properties of brain alkaline phosphatase. J Neurochem, 29, 503-12.
  11. Davis AE, Patterson F (1994). Aspirin reduces the incidence of colonic carcinoma in the dimethylhydrazine rat animal model. Aust. NZJ Med, 24, 301-3.
  12. Ehud JM, Joseph GS, Mordechai C (1983). Copper and zinc levels in normal and malignant tissues. Cancer, 52, 868-72.<868::AID-CNCR2820520521>3.0.CO;2-K
  13. Day DW, Morson BC (1978). The adenoma-carcinoma sequence, In: Morson, B.C. (ed.), The Pathogenesis of Colorectal Cancer, Philadelphia: W. B. Saunders Company. 58-71.
  14. Evans P, Halliwell B (2001). Micronutrients: oxidant/antioxidant status. Br J Nutr, 85, 67-74.
  15. Fabricant M, Broitman SA (1990). The geographical distribution of cancer. Br J Cancer, 23, 1-8.
  16. Farber E, Cameron R (1980). The sequential analysis of cancer development. Adv Cancer Res, 31, 125-226.
  17. Fujimoto S, Misaki F, Kato K (2006). Serum alkaline phosphatase (Al-pase) isozyme in gastric and colonic cancer. Am J Physiol-Gasterol, 290, 737-46.
  18. Furukawa K, Yamanto I, Tanida N, Tsujiai T (1995). The effects of dietary fiber from lagenaria scineraria yugaomelon on colonic carcinogenesis in mice. Cancer, 15, 1508-15.
  19. Grigolo B, Lisignoli G, Toneguzzi S, Mazzetti I (1998). Copper /Zinc Super oxide dismutase expression by different human osteosarcoma cell lines. Anticancer Res, 18, 1175-80
  20. Hambidge KM (1989). Mild zinc deficiency in human subjects. In: Mills, C. (ed.), Zinc in Human Biology. Human Nutrition Reviews, Springer-Verlag, 281-96.
  21. Harmenberg U, Koham M, Koshida K (1991). Identification and Characterization of alkaline phospahatase isoenzymes in human colorectal adenocarcinomas. Tumor Biol, 12, 237-48
  22. Haenszel W, Berg JW, Kurihara M, Locke MB (1973). Large bowel cancer in Hawaian Japanese. J Natl Cancer Inst, 51, 1765-79.
  23. Inagake M, Yamane T, Kitao Y, Oya K (1995). Inhibition of 1, 2 dmh induced oxidative DNA damage. Jpn J Cancer Res, 86, 1106-11.
  24. Inutska S, Araki S (1978). Plasma copper and zinc levels in patients with malignant tumors of digestive organs. Cancer, 42, 626-31.<626::AID-CNCR2820420232>3.0.CO;2-F
  25. Katica BK, Karmen S, Matilda D, Zoran K (2006). Intestinal alkaline phosphatase activity as a molecular marker of enterotoxicity induced by single dose of 5-fluorouracil and protective role of orally administered glutamine. Arch Oncol, 14, 101-5.
  26. Kahnke MJ (1966). Atomic sbsorption spectrophotometry applied to determination of zinc in formalinised human tissue. At Absorption Newsl, 5, 1.
  27. Kim TS, Jung Y, Kim KS (2000). Molecular cloning and expression of copper and zinc containing super-oxide dismutase from Fasciola Hepatica. Infection Immunity, 8, 3941-8.
  28. Katsuyuki Y, Sotaro F, Fumio M, Keiichi K (1978). Serum alkaline phosphatase (Al-pase) isozyme in gastric and colonic cancer. J Gastroenterology, 13, 264-71.
  29. McBean JT, Dove JA, Smith JR, et al (1972). Zinc concentration in human tissues. Am J Clin Nutr, 25, 672-6.
  30. McLellan EA, Bird RP (1988). Aberrant crypts: potential preneoplastic lesions in the murine colon. Cancer Res, 48, 6187-92.
  31. Oberley LW, Buttner GR (1979). Role of super oxide dismutase in cancer. Cancer Res, 39, 1141-9.
  32. Park HS, Goodlad RA, Wright NA (1997). The incidence of aberrant crypt foci and colonic carcinoma in dimethylhydrazine treated rats varies in a site-specific manner and depends on tumor histology. Cancer Res, 57, 507-10.
  33. Reinhold JG, Kfoury GA (1969). Zinc dependent enzyme in zinc depleted rats. Am J Clin Nutr, 22, 1250.
  34. Richards TC (1977). Early changes in the dynamics of crypt cell populations in mouse colon following administration of 1,2-dimethylhydrazine. Cancer Res, 37, 1680-5
  35. Rogers AE, Nauss KM (1985). Rodent models for carcinoma of the colon. Dig Dis Sci, 30, 87-102.
  36. Rosner F, Garfien PC (1968). Erythrocytes and plasma zinc and magnesium levels in health and disease. J Lab Clin Med, 72, 213-?.
  37. Rao DN, Ganesh B (1998). Estiamtes of cancer incidence in India in 1991. Indian J Cancer, 35, 10-18.
  38. Sequeira JL, Kobayasi SK, Rodrigues MM (2000). Early and late effects of wound healing on development of colon tumors in a model of colon carcinogenesis by 1,2 dimethylhydrazine in the rat.Pathology, 32, 250-2.
  39. Sandforth F, Heimpel S, Blazer T, Gutshmidt S (1988). Characterization of stereo microscopically identified preneoplastic lesions during dimethyl hydrazine induced colonic carcinogenesis. Eur J Clin Invest, 6, 655-62.
  40. Vallee BL, Bertini I, Gary (1986). eds. A synopsis of zinc biology and pathology in zinc enzymes Birkhauser Boston.
  41. Vertuani S, Angusti A, Manfredini S (2004). The antioxidants and pro-antioxidants network: an overview. Curr Pharm Des 10, 1677-94
  42. Valcovic V (1980). Analysis of Biologic material for Trace elements using XRay Spectroscopy, Boca Raton FL:CRC Press Inc, 125-43.
  43. Van Driel BE, Lyon H, Hoogenraad DC, et al (1997). Expression of Cu Zn and Mn SOD in human colorectal neoplasm. Free Radic Biol Med, 23, 435-44.
  44. Westman NG, Stefan L, Marklund S (1981). Copper zinc SOD and manganese containing SOD in human tissues and human malignant tumors. Cancer Res, 41, 2962-6.
  45. Zhurkov VS, Sycheva LP, Salamatova O (1996). Selective inhibition of micronuclei in the rat/mouse colon and liver by 1,2-dimethylhydrazine - a seven tissue comparative study. Mut Res, 12, 115-20

Cited by

  1. Zinc and Copper Levels in Bladder Cancer: A Systematic Review and Meta-Analysis vol.153, pp.1-3, 2013,
  2. Serum Copper and Zinc Levels Among Iranian Colorectal Cancer Patients vol.170, pp.2, 2016,
  3. Co-treatment with sulforaphane–zein microparticles enhances the chemopreventive potential of zinc in a 1,2-dimethylhydrazine induced colon carcinogenesis rat model vol.6, pp.41, 2016,