Skip to main content
Biochemical Journal logoLink to Biochemical Journal
. 1994 Jun 15;300(Pt 3):799–803. doi: 10.1042/bj3000799

The effect of iron overload on rat plasma and liver oxidant status in vivo.

A J Dabbagh 1, T Mannion 1, S M Lynch 1, B Frei 1
PMCID: PMC1138237  PMID: 8010963

Abstract

There is ample evidence implicating reactive oxygen species in a number of human degenerative diseases such as atherosclerosis and haemochromatosis. Although lipid peroxidation underlies many of the toxic effects of oxidative stress, there is a lack of a sensitive and reliable method for its assessment in vivo. To understand the implications of oxidative stress in vivo, we have used dietary iron overload (IO) in the rat. Oxidant status in these animals was determined by assessing depletion of endogenous antioxidants and formation of various lipid peroxidation products, including acylated F2-isoprostanes, a novel class of free-radical-derived prostaglandin-F2-like compounds. IO led to a significant decrease in the concentration of the antioxidants alpha-tocopherol and ascorbic acid in plasma, and alpha-tocopherol, beta-carotene and ubiquinol-10 in liver. Whereas there was no significant lipid peroxidation in plasma, hepatic F2-isoprostane levels were moderately but significantly increased in IO. In addition, IO caused a significant increase in plasma total and high-density lipoprotein cholesterol levels, an effect that was correlated with depletion of plasma ascorbic acid but not alpha-tocopherol. The data demonstrate that IO causes lipid metabolism disturbances and oxidative stress which is associated with substantial depletion of endogenous antioxidants and moderate lipid peroxidative damage.

Full text

PDF
799

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bacon B. R., Brittenham G. M., Tavill A. S., McLaren C. E., Park C. H., Recknagel R. O. Hepatic lipid peroxidation in vivo in rats with chronic dietary iron overload is dependent on hepatic iron concentration. Trans Assoc Am Physicians. 1983;96:146–154. [PubMed] [Google Scholar]
  2. Bacon B. R., Britton R. S., O'Neill R. Effects of vitamin E deficiency on hepatic mitochondrial lipid peroxidation and oxidative metabolism in rats with chronic dietary iron overload. Hepatology. 1989 Mar;9(3):398–404. doi: 10.1002/hep.1840090309. [DOI] [PubMed] [Google Scholar]
  3. Bacon B. R., Britton R. S. The pathology of hepatic iron overload: a free radical--mediated process? Hepatology. 1990 Jan;11(1):127–137. doi: 10.1002/hep.1840110122. [DOI] [PubMed] [Google Scholar]
  4. Bieri J. G., Evarts R. P., Thorp S. Factors affecting the exchange of tocopherol between red blood cells and plasma. Am J Clin Nutr. 1977 May;30(5):686–690. doi: 10.1093/ajcn/30.5.686. [DOI] [PubMed] [Google Scholar]
  5. Björkhem I., Kallner A. Hepatic 7alpha-hydroxylation of cholesterol in ascorbate-deficient and ascorbate-supplemented guinea pigs. J Lipid Res. 1976 Jul;17(4):360–365. [PubMed] [Google Scholar]
  6. Blakely S. R., Mitchell G. V., Jenkins M. Y., Grundel E., Whittaker P. Canthaxanthin and excess vitamin A alter alpha-tocopherol, carotenoid and iron status in adult rats. J Nutr. 1991 Oct;121(10):1649–1655. doi: 10.1093/jn/121.10.1649. [DOI] [PubMed] [Google Scholar]
  7. Brissot P., Deugnier Y., Le Treut A., Regnouard F., Simon M., Bourel M. Ascorbic acid status in idiopathic hemochromatosis. Digestion. 1978;17(6):479–487. doi: 10.1159/000198154. [DOI] [PubMed] [Google Scholar]
  8. Britton R. S., Bacon B. R., Recknagel R. O. Lipid peroxidation and associated hepatic organelle dysfunction in iron overload. Chem Phys Lipids. 1987 Nov-Dec;45(2-4):207–239. doi: 10.1016/0009-3084(87)90066-1. [DOI] [PubMed] [Google Scholar]
  9. Burkitt M. J., Mason R. P. Direct evidence for in vivo hydroxyl-radical generation in experimental iron overload: an ESR spin-trapping investigation. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8440–8444. doi: 10.1073/pnas.88.19.8440. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cohen A., Cohen I. J., Schwartz E. Scurvy and altered iron stores in thalassemia major. N Engl J Med. 1981 Jan 15;304(3):158–160. doi: 10.1056/NEJM198101153040307. [DOI] [PubMed] [Google Scholar]
  11. Cunnane S. C., McAdoo K. R. Iron intake influences essential fatty acid and lipid composition of rat plasma and erythrocytes. J Nutr. 1987 Sep;117(9):1514–1519. doi: 10.1093/jn/117.9.1514. [DOI] [PubMed] [Google Scholar]
  12. Frei B., England L., Ames B. N. Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6377–6381. doi: 10.1073/pnas.86.16.6377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Frei B., Kim M. C., Ames B. N. Ubiquinol-10 is an effective lipid-soluble antioxidant at physiological concentrations. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4879–4883. doi: 10.1073/pnas.87.12.4879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Frei B., Stocker R., Ames B. N. Antioxidant defenses and lipid peroxidation in human blood plasma. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9748–9752. doi: 10.1073/pnas.85.24.9748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gutteridge J. M. Thiobarbituric acid-reactivity following iron-dependent free-radical damage to amino acids and carbohydrates. FEBS Lett. 1981 Jun 15;128(2):343–346. doi: 10.1016/0014-5793(81)80113-5. [DOI] [PubMed] [Google Scholar]
  16. Halliwell B., Gutteridge J. M. Formation of thiobarbituric-acid-reactive substance from deoxyribose in the presence of iron salts: the role of superoxide and hydroxyl radicals. FEBS Lett. 1981 Jun 15;128(2):347–352. doi: 10.1016/0014-5793(81)80114-7. [DOI] [PubMed] [Google Scholar]
  17. Heinecke J. W., Rosen H., Chait A. Iron and copper promote modification of low density lipoprotein by human arterial smooth muscle cells in culture. J Clin Invest. 1984 Nov;74(5):1890–1894. doi: 10.1172/JCI111609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Katoh S., Toyama J., Kodama I., Akita T., Abe T. Deferoxamine, an iron chelator, reduces myocardial injury and free radical generation in isolated neonatal rabbit hearts subjected to global ischaemia-reperfusion. J Mol Cell Cardiol. 1992 Nov;24(11):1267–1275. doi: 10.1016/0022-2828(92)93093-y. [DOI] [PubMed] [Google Scholar]
  19. Loeb L. A., James E. A., Waltersdorph A. M., Klebanoff S. J. Mutagenesis by the autoxidation of iron with isolated DNA. Proc Natl Acad Sci U S A. 1988 Jun;85(11):3918–3922. doi: 10.1073/pnas.85.11.3918. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Maioli M., Pettinato S., Cherchi G. M., Giraudi D., Pacifico A., Pupita G., Tidore M. G. Plasma lipids in beta-thalassemia minor. Atherosclerosis. 1989 Feb;75(2-3):245–248. doi: 10.1016/0021-9150(89)90182-2. [DOI] [PubMed] [Google Scholar]
  21. Matsura T., Yamada K., Kawasaki T. Changes in the content and intracellular distribution of coenzyme Q homologs in rabbit liver during growth. Biochim Biophys Acta. 1991 Jun 3;1083(3):277–282. doi: 10.1016/0005-2760(91)90083-t. [DOI] [PubMed] [Google Scholar]
  22. Matsura T., Yamada K., Kawasaki T. Difference in antioxidant activity between reduced coenzyme Q9 and reduced coenzyme Q10 in the cell: studies with isolated rat and guinea pig hepatocytes treated with a water-soluble radical initiator. Biochim Biophys Acta. 1992 Feb 12;1123(3):309–315. doi: 10.1016/0005-2760(92)90012-k. [DOI] [PubMed] [Google Scholar]
  23. Morrow J. D., Awad J. A., Kato T., Takahashi K., Badr K. F., Roberts L. J., 2nd, Burk R. F. Formation of novel non-cyclooxygenase-derived prostanoids (F2-isoprostanes) in carbon tetrachloride hepatotoxicity. An animal model of lipid peroxidation. J Clin Invest. 1992 Dec;90(6):2502–2507. doi: 10.1172/JCI116143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Morrow J. D., Harris T. M., Roberts L. J., 2nd Noncyclooxygenase oxidative formation of a series of novel prostaglandins: analytical ramifications for measurement of eicosanoids. Anal Biochem. 1990 Jan;184(1):1–10. doi: 10.1016/0003-2697(90)90002-q. [DOI] [PubMed] [Google Scholar]
  25. Nichols G. M., Bacon B. R. Hereditary hemochromatosis: pathogenesis and clinical features of a common disease. Am J Gastroenterol. 1989 Aug;84(8):851–862. [PubMed] [Google Scholar]
  26. Odumosu A., Wilson C. W. Tissue ascorbic acid, fenfluramine, and changes in fat metabolism. Int J Obes. 1979;3(2):123–131. [PubMed] [Google Scholar]
  27. Palozza P., Krinsky N. I. Antioxidant effects of carotenoids in vivo and in vitro: an overview. Methods Enzymol. 1992;213:403–420. doi: 10.1016/0076-6879(92)13142-k. [DOI] [PubMed] [Google Scholar]
  28. Park C. H., Bacon B. R., Brittenham G. M., Tavill A. S. Pathology of dietary carbonyl iron overload in rats. Lab Invest. 1987 Nov;57(5):555–563. [PubMed] [Google Scholar]
  29. Persijn J. P., van der Slik W., Riethorst A. Determination of serum iron and latent iron-binding capacity (LIBC). Clin Chim Acta. 1971 Nov;35(1):91–98. doi: 10.1016/0009-8981(71)90298-1. [DOI] [PubMed] [Google Scholar]
  30. Rice-Evans C., McCarthy P., Hallinan T., Green N. A., Gor J., Diplock A. T. Iron overload and the predisposition of cells to antioxidant consumption and peroxidative damage. Free Radic Res Commun. 1989;7(3-6):307–313. doi: 10.3109/10715768909087956. [DOI] [PubMed] [Google Scholar]
  31. Rubiés-Prat J., Masdeu S., Nubiola A. R., Chacón P., Holguera C., Masana L. High-density lipoprotein cholesterol and phospholipids, and apoprotein A in serum of patients with liver disease. Clin Chem. 1982 Mar;28(3):525–527. [PubMed] [Google Scholar]
  32. Salonen J. T., Nyyssönen K., Korpela H., Tuomilehto J., Seppänen R., Salonen R. High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Circulation. 1992 Sep;86(3):803–811. doi: 10.1161/01.cir.86.3.803. [DOI] [PubMed] [Google Scholar]
  33. Stocker R., Bowry V. W., Frei B. Ubiquinol-10 protects human low density lipoprotein more efficiently against lipid peroxidation than does alpha-tocopherol. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1646–1650. doi: 10.1073/pnas.88.5.1646. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Stål P., Hultcrantz R. Iron increases ethanol toxicity in rat liver. J Hepatol. 1993 Jan;17(1):108–115. doi: 10.1016/s0168-8278(05)80530-6. [DOI] [PubMed] [Google Scholar]
  35. Thurnham D. I., Davies J. A., Crump B. J., Situnayake R. D., Davis M. The use of different lipids to express serum tocopherol: lipid ratios for the measurement of vitamin E status. Ann Clin Biochem. 1986 Sep;23(Pt 5):514–520. doi: 10.1177/000456328602300505. [DOI] [PubMed] [Google Scholar]
  36. Turley S. D., West C. E., Horton B. J. The role of ascorbic acid in the regulation of cholesterol metabolism and in the pathogenesis of artherosclerosis. Atherosclerosis. 1976 Jul-Aug;24(1-2):1–18. doi: 10.1016/0021-9150(76)90060-5. [DOI] [PubMed] [Google Scholar]
  37. Wapnick A. A., Bothwell T. H., Seftel H. The relationship between serum ion levels and ascorbic acid stores in siderotic Bantu. Br J Haematol. 1970 Aug;19(2):271–276. doi: 10.1111/j.1365-2141.1970.tb01624.x. [DOI] [PubMed] [Google Scholar]
  38. Wapnick A. A., Lynch S. R., Krawitz P., Seftel H. C., Charlton R. W., Bothwell T. H. Effects of iron overload on ascorbic acid metabolism. Br Med J. 1968 Sep 21;3(5620):704–707. doi: 10.1136/bmj.3.5620.704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Yamamoto Y., Frei B., Ames B. N. Assay of lipid hydroperoxides using high-performance liquid chromatography with isoluminal chemiluminescence detection. Methods Enzymol. 1990;186:371–380. doi: 10.1016/0076-6879(90)86130-n. [DOI] [PubMed] [Google Scholar]
  40. Yamamoto Y., Komuro E., Niki E. Antioxidant activity of ubiquinol in solution and phosphatidylcholine liposome. J Nutr Sci Vitaminol (Tokyo) 1990 Oct;36(5):505–511. doi: 10.3177/jnsv.36.505. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES