Anticarcinogenic Effect and Modification of Cytochrome P450 2E1 by Dietary Garlic Powder in Diethylnitrosamine-Initiated Rat Hepatocarcinogenesis

  • Park, Kyung-Ae (School of Human Ecology, Kaya University) ;
  • Kweon, Sang-Hui (Department of Food and Nutrition, Seoul National University) ;
  • Choi, Hay-Mie (Department of Food and Nutrition, Seoul National University)
  • Published : 2002.11.30


The purpose of this study was to determine the effects of dietary garlic powder on diethylnitrosamine (DEN)-induced hepatocarcinogenesis and cytochrome P450 (CYP) enzymes in weaning male Sprague-Dawley rats by using the medium-term bioassay system of Ito et al. The rats were fed diets that contained 0, 0.5, 2.0 or 5.0% garlic powder for 8 weeks, beginning the diets with the intraperitoneal (i.p.) injection of DEN. The areas of placental glutathione S-transferase (GST-P) positive foci, an effective marker for DEN-initiated lesions, were significantly decreased in the rats that were fed garlic-powder diets; the numbers were significantly decreased only in the 2.0 and 5.0% garlic-powder diets. The p-nitrophenol hydroxylase (PNPH) activities and protein levels of CYP 2E1 in the hepatic microsomes of the rats that were fed the 2.0 and 5.0% garlic powder diet were much lower than those of the basal-diet groups. Pentoxyresorufin O-dealkylase (PROD) activity and CYP 2B1 protein level were not influenced by the garlic-powder diets and carcinogen treatment. Therefore, the suppression of CYP 2E1 by garlic in the diet might influence the formation of preneoplastic foci during hepatocarcinogenesis in rats that are initiated with DEN.



  1. Agarwal, K. C. (1996) Therapeutic actions of garlic constituents. Medical Research Review 16, 111-124.<111::AID-MED4>3.0.CO;2-5
  2. Alnaqeeb, M. A., Thomson, M., Brodia, T. and Ali, M. (1996) Histopathological effects of garlic on liver and lung of rats. Toxicol. Lett. 85, 157-164.
  3. Baginski, E. S., Foa, P. P. and Zak, B. (1983) Glucose 6- phosphatase. Methods of Enzymatie Analysis vol. 2, 876-880.
  4. Brady, J. F., Wang, M-H., Hong, J-Y., Xiao, F., Li, Y., Yoo, J-S. H., Ning, S.M., Lee, M-J., Fukuto, J. M., Gapac, J. M. and Yang, C. S. (1991) Modulation of rat hepatic microsomal monooxygenase enzymes and cytotoxicity by diallyl sulfide. Toxicol. Appl. Pharmaeol. 108, 342-354.
  5. Buege, J. A. and Aust, S. D. (1978) Microsomal lipid peroxidation. Methods Enzymol. 52, 302-310.
  6. Burke, M. D., Thompson, S., Elcombe, C. R., Halpert, J., Haaparanta, T.,and Mayer, R. T. (1985) Ethoxy-, pentoxy-, benzyloxyphenoxazones and homologues: A series of substrates to distinguish between different induced cytochrome P-450. Biochem. Phannacol. 34, 3337-3345.
  7. Cheng, J-Y., Meng, C-L., Tzeng, C-C. and Lin, J-C. (1995) Optimal dose of garlic to inhibit dimethylhydrazine-induced colon cancer. World J. Surg. 19, 621-626.
  8. Fleischauer, A. T., Poole, C. and Arab, L. (2000) Garlic consumption and cancer prevention: meta-analyses of colorectal and stomach cancers. Am. J. Clin. Nutr. 72, 1047-1052.
  9. Fukushima, S., Takada, N., Hori, T. and Wanibuchi, H. (1998) Cancer prevention by organosulfur compounds from garlic and onion. J. Cell Biochem. (Suppl.) 27, 100-205.
  10. Guengerich, F. P., Dannan, G. A., Wright, S. T., Martin, M. V. and Kaminsky, L. S. (1982) Purification and characterization of rat liver microsomal cytochrome P450: electrophoretic, spectral, catalytic and immunochemical properties and inducibility of 8 isozymes isolated from rats treated with phenobarbital or $\beta$-naphtoflavone. Biochemistry. 21, 6019-6030.
  11. Haber, D., Siess, M-H., De Waziers, J., Beaune, P. and Suschetet, M. (1994) Modification of hepatic drug-metabolizing enzymes in rat fed naturally occurring allyl sulfides. Xenohiotica 24, 169-182.
  12. Harber-Mignard, D., Suschetet, M., Berges, R, Astorg, P. and Siess, M. H. (1996) Inhibition of aflatoxin B1- and N-nitrosodiethylarnine-induced liver preneoplastic foci in rats fed naturally occurring allyl sulfides. Nutr. Cancer 35, 61-70.
  13. Hsu, S.-M., Raine, L. and Fanger, H. (1981) Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: A comparison between ABC and unlabeled antibody (PAP) procedure. J. Histochem. Cytochem. 29, 577-580.
  14. Ito, N., Tsuda, H., Tatematsu, M., Inoue, T., Tagawa, Y., Aoki, T., Uwagawa, S., Kagawa, M., Ogiso, T., Masui, T., Imaida, K, Fukushima, S. and Asamoto, M. (1988) Enhancing effect of various hepatocarcinogens on induction of preneoplastic S-transferase placental form positive foci in rats-an approach for a new medium-term bioassay system. Carcinogenesis 9, 387- 394.
  15. Jang, J. J., Cho, K. J. and Kim, S. H. (1989) Effects of allyl sulfide, germanium and NaCl on the development of glutathione S-transferase P-positive rat hepatic foci initiated by diethylnitrosamine. Anticancer Res. 9, 273-275.
  16. Kagawa, K., Matsutaka, H., Yamaguch, Y. and Fukuhama, C. (1986) Garlic extract inhibits the enhanced peroxidation and production of lipids in carbon tetrachloride-induced liver injury. Jpn. J. Pharmacol. 42, 19-26.
  17. Kim, S. H. and Choi, H. (1997) Effect of N-6, N-3 fatty acids and vitamin E supplement on the induction of preneoplastic lesion in murine hepatocarcinogenesis. J. Biochem. Mol. Biol. 27, 125-131.
  18. Korea National Statistical Office (2000)
  19. Kwak, M. K., Kim, S. G. and Kim, N. D. (1995) Effects of garlic oil on rat hepatic P450 2E1 expression. Xenobiotica 25, 1021- 1029.
  20. Kweon, S., Kim, Y., Choj, H., Kwon, W. J. and Chang, K. J. (2000) Excess taurine induced placental glutathione S-transferase positive foci formation in rat. J Biochem. Mol. Biol. 33, 469-475.
  21. Lammli, U. K. (1970) Cleavage of structural proteins during assembly of the head the bacteriophage T4. Nature 227, 680- 685.
  22. Lowry, O. H., Rosebrough, N. L., Farr, A. L. and Randall, R. T. (1951) Protein measurement with the folin phenol reagent. J. Biol. Chem. 193, 265-275.
  23. Meng, C. L. and Shyu, K.W. (1990) Inhibition of experimental carcinogenesis by painting with garlic extract. Nutr. Cancer 14, 207-217.
  24. Nakagawa, S., Masamoto, K., Sumiyoshi, H. and Harada, H. (1984) Acute toxicity test of garlic extract. J. Toxicol. Sci. 9, 57-60.
  25. Omura, T. and Sato, R. (1964) The carbon monooxide-binding pigment of liver microsomes: I. Evidence for its hemoprotein nature. J. BioI. Chem. 239, 2370-2378.
  26. Park, K. A. and Choi, H. (1997) Modification of hepatic microsomal cytochrome P450 2EI enzyme by garlic powder in rat hepalocarcinogenesis. J. Biochem. Mol, Biol. 30, 73-79.
  27. Park, E.-M., Park, J.-S., Kim, Y.-J., Sung, J. S., Hwang, T.-S., Kim, W.-C., Han, M.-Y. and Park, Y.-M. (2001) Role of oxidative stress in the radiation-induced lung pathogenesis in mice. J. Biochem. Mol. BioI. 34, 544-550.
  28. Reicks, M. M. and Crankshaw, D. L. (1996) Modulation of rat hepatic cytochrome P450 activity by garlic organosulfur compounds. Nutr. Cancer 25, 241-248.
  29. Reinke, L. A. and Moyer, M. J. (1995) p-Nitrophenol hydroxylation. A microsomal oxidation which is highly inducible by ethanol. Drug Meta. Diopo. 13, 548-552.
  30. Rowe, L. and Wills, E. D, (1976) The effect of dietary lipids vitamin E on lipid peroxide formation, cytochrome P-450 and oxidative demethylation in the endoplasmic reticulum. Biochem. Phamlacol. 15, 175-179.
  31. Samaranayake, M. D. P., Wickrarnasinghe, S. M. D. N., Angunawela, p., Jayasekera, S., lwai, S. and Fukushima, S. (2000) Inhibition of chemically induced liver carcinogenesis in Wistar rats by garlic (Allium sativum). Phytother. Res. 14, 564- 467.<564::AID-PTR664>3.0.CO;2-Z
  32. Sato, K., Kitahara, A., Satoh. K, Ishikawa, T., Tatematsu, M. et al. (1984) The placental form of glutathione S-transferase as a new marker protein for preneoplasia in rat chemical hepatocarcinogenesis. Jpn. J. Cancer Res. 75, 199-202.
  33. Satoh, K., Kitahara, A., Soma, Y., Inaba, Y., Hatayarna, I. and Sato. K (1985) Purification, induction, and distribution of placental glutathione transferase: A new marker enzyme for preneoplastic cells in the rat chemical hepatocarcinogenesis. Proc. Natl. Acad. Sci. USA 82, 3964-3968.
  34. Schaffer, E. M., Liu, J-Z. and Milner, J. A. (1997) Garlic powder and allyl sulfur compounds enhance the ability of dietary selenite to inhibit 7.l2-dimethyIbenz[a]-anthracene-induced mammary DNA adducts. Nutr. Cancer 27. 162-168.
  35. Schorah, C. J. (1999) Micronutrients, vitamins, and cancer risk. VIiam. Honn. 57, 1-23.
  36. Sheen, L,Y., Cben, H.-W., Kung, Y.-L., Liu, C.-T. and Lii, C.-K. (1999) Effect of garlic oil and its organosulfur compounds on the activities of hepatic drug-metabolizing and antioxidant enzymes in rats fed high- and low-fat diets. Nutr. Cancer 35, 160-166.
  37. Siess, M. H., Le Bon, A. M., Canivenc-Lavier, M. C. and Suschetet, M. (1997) Modification of hepatic drug-metabolizing enzymes in rats treated with alkyl sulfides. Cancer lett. 120, 195-201.
  38. Slngh, A. and Shukla, Y. (1998) Antitumor activity of diallyl sulfide in two-stage mouse skin model of carcinogenesis. Biomed. Environ. Sci. 11. 258-263.
  39. Takada, N., Matsuda, T., Otashi, T., Yano, Y., Otani, S., Hasegawa. T., Nnkae. D., Konishi, Y. and Fukushima, S. (1994) Enhancement by organosulfur compounds from garlic and onions of diethylnitrosamine-induced glutathione S-transferase positive foci in the rat liver. Cancer Res. 54, 2895-2899.
  40. Wargovich, M. J ., Woods, C., Eng, V. W. S., Stephens, C. and Gray, K. (1988) Chemoprevention of N-nitrosomethylbenzylarnine- induced esophageal cancer in rats by the naturally occurring thioether, diallyl sulfide. Cancer Res. 48, 6872-6875.

Cited by

  1. Modulation of Metabolic Detoxification Pathways Using Foods and Food-Derived Components: A Scientific Review with Clinical Application vol.2015, 2015,
  2. Role of Spices Beyond Food Flavoring: Nutraceuticals with Multiple Health Effects vol.21, pp.2, 2005,
  3. Garlic: Health benefits and actions vol.2, pp.1, 2012,
  4. Sodium butyrate induces apoptosis in human hepatoma cells by a mitochondria/caspase pathway, associated with degradation of β-catenin, pRb and Bcl-XL vol.40, pp.9, 2004,
  5. Inhibitory effects and molecular mechanisms of garlic organosulfur compounds on the production of inflammatory mediators vol.57, pp.11, 2013,
  6. Signal transduction pathways leading to cell cycle arrest and apoptosis induction in cancer cells by Allium vegetable-derived organosulfur compounds: a review vol.555, pp.1-2, 2004,
  7. Antithrombotic and anticancer effects of garlic-derived sulfur compounds: A review vol.26, pp.2, 2006,
  8. Nuclear Receptors in Drug Metabolism, Drug Response and Drug Interactions vol.2, 2015,
  9. Phytochemicals as potential chemopreventive and chemotherapeutic agents in hepatocarcinogenesis vol.18, pp.1, 2009,
  10. N-Nitrosodiethylamine-Induced Pig Liver Hepatocellular Carcinoma Model: Radiological and Histopathological Studies vol.29, pp.3, 2006,
  11. Potential role of organic sulfur compounds from Allium species in cancer prevention and therapy vol.8, pp.2, 2009,