Skip to main content
SpringerLink
Log in

Effect of dietary vitamin E on the development of altered hepatic foci and hepatic tumors induced by the peroxisome proliferator ciprofibrate

  • Original Papers
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Summary

The purpose of this study was to determine the effect of the dietary antioxidant vitamin E on hepatocarcinogenesis by peroxisome proliferators which, it is hypothesized, induce tumors by increased production of hydrogen peroxide or other oxygen radicals. Rats were fed diets containing the peroxisome proliferator ciprofibrate and one of three concentrations (10, 50, or 500 ppm) ofα-tocopheryl acetate for 6 months or 21 months. The incidence of hepatic tumors and the number and volume ofγ-glutamyl-transpeptidase-positive, ATPase-negative, glucose-6-phosphatase-negative, and glucose-6-phosphatase-positive foci were quantified. No tumors or altered hepatic foci were seen at 6 months, but at 21 months the incidence of hepatic tumors and the number and volume of altered hepatic foci were increased in rats fed higher levels of vitamin E. Indices of oxidative damage — concentrations of malonaldehyde, conjugated dienes, and lipidsoluble fluorescence products — were not affected or were lower in rats fed higher amounts of vitamin E; the enhancing effect of vitamin E on the development of altered hepatic foci and hepatic tumors, therefore, was not related to the induction of cellular oxidative damage. Hepatic peroxisomal fatty acidΒ-oxidation and vitamin C concentrations were not affected by vitamin E, whereas the glutathione concentration was decreased in rats fed higher amounts of vitamin E. This study shows that increasing the vitamin E content of the diet enhances ciprofibrate-induced hepatocarcinogenesis, but the mechanism of this effect is unclear.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

GGT:

γ-glutamyl transpeptidase

G6Pase:

glucose-6-phosphatase

References

  • Bieri JG (1980) Second report of the ad hoc committee on standards for nutritional studies. J Nutr 110:1726

    Google Scholar 

  • Bieri JG, Stoewsand GS, Briggs GM, Phillips RW, Woodard JC, Knapka JJ (1977) Report of the American Institute of Nutrition ad hoc committee on standards for nutritional studies. J Nutr 107:1340–1348

    Google Scholar 

  • Campbell HA, Pitot HC, Potter VR, Laishes BA (1982) Application of quantitative stereology to the evaluation of enzyme-altered foci in rat liver. Cancer Res 42:465–472

    Google Scholar 

  • Campbell HA, Xu YD, Hanigan MH, Pitot HC (1986) Application of quantitative stereology to the evaluation of phenotypically heterogeneous enzyme-altered foci in the rat liver. J Natl Cancer Inst 76:751–767

    Google Scholar 

  • Cattley RC, Popp JA (1989) Differences between the promoting activities of the peroxisome proliferator Wy-14,643g and phenobarbital in rat liver. Cancer Res 49:3246–3251

    Google Scholar 

  • Changchit C, Chow CK (1988) Measurement of malonaldehyde in biological systems by high performance liquid chromatography (HPLC) with fluorescence detection. FASEB J 2:A406

    Google Scholar 

  • Chen LH, Boissonneault GA, Glauert HP (1988) Vitamin C, vitamin E and cancer (review). Anticancer Res 8:739–748

    Google Scholar 

  • Chow CK (1979) Nutritional influence on cellular antioxidant defense systems. Am J Clin Nutr 32:1066–1081

    Google Scholar 

  • Draper HH, Csallany AS (1969) A simplified hemolysis test for vitamin E deficiency. J Nutr 98:390–394

    Google Scholar 

  • Enzmann H, Ohlhauser D, Enzmann H, Dettler T, Benner U, Hacker HJ, Bannasch P (1989) Unusual histochemical pattern in preneoplastic hepatic foci characterized by hyperactivity of several enzymes. Virchows Arch [B] 57:99–108

    Google Scholar 

  • Gill JL (1978) Design and analysis of experiments in the animal and medical sciences, vol 1. Iowa State University Press, Ames

    Google Scholar 

  • Glauert HP, Clark TD (1989) Lack of initiating activity of the peroxisome proliferator ciprofibrate in two-stage hepatocarcinogenesis. Cancer Lett 43:95–100

    Google Scholar 

  • Glauert HP, Pitot HC (1986) Influence of dietary fat on the promotion of diethylnitrosamine-induced hepatocarcinogenesis in female rats. Proc Soc Exp Biol Med 181:498–506

    Google Scholar 

  • Glauert HP, Beer D, Rao MS, Schwarz M, Xu YD, Goldsworthy TL, Coloma J, Pitot HC (1986) Induction of altered hepatic foci in rats by the administration of hypolipidemic peroxisome proliferators alone or following a single dose of diethylnitrosamine. Cancer Res 46:4601–4606

    Google Scholar 

  • Hatam LJ, Kayden HJ (1979) A high-performance liquid Chromatographic method for the determination of tocopherol in plasma and cellular elements of the blood. J Lipid Res 20:639–645

    Google Scholar 

  • Hawkins JM, Jones WE, Bonner FW, Gibson GG (1987) The effect of peroxisome proliferators on microsomal, peroxisomal, and mitochondrial enzyme activities in the liver and kidney. Drug Metab Rev 18:441–515

    Google Scholar 

  • Hollander M, Wolfe DA (1973) Nonparametric statistical methods. Wiley, New York

    Google Scholar 

  • Kahl R (1986) The dual role of antioxidants in the modification of chemical carcinogenesis. J Environ Sci Health C 4:47–92

    Google Scholar 

  • Lake BG, Evans JG, Walters DG, Price RJ (1990) Comparison of the hepatic effects of nafenopin, a peroxisome proliferator, in rats fed adequate or vitamin E and selenium deficient diets. Toxicologist 10:138

    Google Scholar 

  • Lalwani ND, Reddy MK, Qureshi SA, Reddy JK (1981) Development of hepatocellular carcinomas and increased peroxisomal fatty acidΒ-oxidation in rats fed [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid (Wy-14,643) in the semipurified diet. Carcinogenesis 2:645–650

    Google Scholar 

  • Lazarow PB (1981) Assay of peroxisomalΒ-oxidation of fatty acids. Methods Enzymol 72:315–319

    Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    Google Scholar 

  • Maronpot RR, Montgomery CA Jr, Boorman GA, McConnell EE (1986) National toxicology program nomenclature for hepatoproliferative lesions of rats. Toxicol Pathol 14:263–273

    Google Scholar 

  • McCay PB (1985) Vitamin E: interactions with free radicals and ascorbate. Ann Rev Nutr 5:323–340

    Google Scholar 

  • Medinsky MA, Popp JA, Hamm TE, Dent JG (1982) Development of hepatic lesions in male Fischer-344 rats fed AIN-76A purified diet. Toxicol Appl Pharmacol 62:111–120

    Google Scholar 

  • Newberne PM, Fox JG (1980) Nutritional adequacy and quality control of rodent diets. Lab Anim Sci 30:352–365

    Google Scholar 

  • Omaye ST, Turnbull JD, Sauberlich HE (1979) Selected methods for the determination of ascorbic acid in animal cells, tissues, and fluids. Methods Enzymol 62:3–11

    Google Scholar 

  • Peto R, Pike MC, Day NE, Gray RG, Lee PN, Parish S, Peto J, Richards S, Wahrendorf J (1980) Guidelines for simple, sensitive significance tests for carcinogenic effects in long-term animal experiments. In: Long-term and short-term screening assays for carcinogens: a critical appraisal. IARC Monographs [Suppl 2], annex. IARC, Lyon, pp 311–426

    Google Scholar 

  • Rao MS, Lalwani ND, Watanabe TK, Reddy JK (1984) Inhibitory effect of the antioxidants ethoxyquin and 2(3)-tert-butyl-4-hydroxyanisole on hepatic tumorigenesis in rats fed ciprofibrate, a peroxisome proliferator. Cancer Res 44:1072–1076

    Google Scholar 

  • Recknagel RO, Ghoshal AK (1966) Quantitative estimation of peroxidative degeneration of rat liver microsomal and mitochondrial lipids after carbon tetrachloride poisoning. Exp Mol Pathol 5:413–426

    Google Scholar 

  • Reddy JK, Lalwani ND (1983) Carcinogenesis by hepatic peroxisome proliferators: evaluation of the risk of hypolipidemic drugs and industrial plasticizers to humans. CRC Crit Rev Toxicol 12:1–58

    Google Scholar 

  • Reddy K, Fletcher B, Tappel AL (1973) Measurement and spectral characteristics of fluorescent pigments in tissue of rats as a function of dietary polyunsaturated fats and vitamin E. J Nutr 103:908–915

    Google Scholar 

  • Rutenberg AM, Kim H, Fischbein JW, Hawker JS, Wasserkrug HL, Saligman AM (1969) Histochemical and ultrastructural demonstration of gamma-glutamyl transpeptidase activity. J Histochem Cytochem 17:517–526

    Google Scholar 

  • Sedlack J, Lindsay RH (1968) Estimations of total protein-bound and non-protein sulfhydryl groups is tissues with Ellman's reagent. Anal Biochem 25:192–205

    Google Scholar 

  • Wachstein M, Meisel E (1956) On the histochemical demonstration of glucose-6-phosphatase. J Histochem 4:492

    Google Scholar 

  • Wachstein M, Meisel E (1957) Histochemistry of hepatic phosphatases at a physiologic pH. Am J Clin Pathol 27:13–23.

    Google Scholar 

  • Wendel A, Jaeschke H (1988) Influences of selenium deficiency and glutathione status on liver metabolism. In: Chow CK (ed) Cellular antioxidant defense mechanisms, vol 2. CRC Press, Boca Raton, pp 133–147

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Nutrition and Food Science, University of Kentucky, 212 Funkhouser Bldg., 40506-0054, Lexington, KY, USA

    Howard P. Glauert, Mark M. Beaty, Wendy S. Greenwell, Terri L. Clark, Suseela R. Srinivasan & Ching K. Chow

  2. Department of Pathology, Veterans Administration Hospital, University of Kentucky, 40506, Lexington, KY, USA

    Terry D. Clark

  3. Graduate Center for Toxicology, University of Kentucky, 40506, Lexington, KY, USA

    Howard P. Glauert, Vickie Tatum, Li -Chuan Chen, Tim Borges & Ching K. Chow

Authors
  1. Howard P. Glauert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark M. Beaty
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Terry D. Clark
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wendy S. Greenwell
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vickie Tatum
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Li -Chuan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tim Borges
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Terri L. Clark
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Suseela R. Srinivasan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ching K. Chow
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Supported by American Institute for Cancer Research grant 86B66 and National Cancer Institute grant CA43719.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Glauert, H.P., Beaty, M.M., Clark, T.D. et al. Effect of dietary vitamin E on the development of altered hepatic foci and hepatic tumors induced by the peroxisome proliferator ciprofibrate. J Cancer Res Clin Oncol 116, 351–356 (1990). https://doi.org/10.1007/BF01612917

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01612917

Key words

Search

Navigation