Abstract
The endogenous defenses of the mouse heart against reactive oxygen metabolites were investigated. The activities of three enzymes capable of detoxifying activated oxygen were determined in both the heart and liver; cardiac muscle contains 150 times less catalase and nearly four times less superoxide dismutase than liver. Glutathione peroxidase activities were, however, similar to the two tissues. Assay of glutathione peroxidase in the heart after 6 wk of selenium depletion with both hydrogen peroxide and cumene hydroperoxide as substrates revealed a >80% drop in enzyme activity and gave no indication that murine cardiac tissue contains nonselenium-dependent glutathione peroxidase. The selenium-deficient state, which was characterized by markedly decreased cardiac glutathione peroxidase levels, led to significantly enhanced doxorubicin toxicity at a dose of 15 mg/kg i.p.
Doxorubicin administration in selenium-sufficient animals resulted in a dose-dependent decrease in cardiac glutathione peroxidase activity; the decrease in enzyme activity lasted 72 h after 15 mg/kg i.p. In contrast, cardiac superoxide dismutase and hepatic superoxide dismutase and glutathione peroxidase were unaffected by this dose of doxorubicin.
These results suggest that the major pathway in cardiac tissue for detoxification of reactive oxygen metabolites is via the concerted action of superoxide dismutase and selenium-dependent glutathione peroxidase. The latter enzyme may be depleted by a selenium-deficient diet or doxorubicin treatment, leaving the heart with limited mechanisms for disposing of hydrogen peroxide or lipid peroxides.
Full text
PDF







Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Awasthi Y. C., Beutler E., Srivastava S. K. Purification and properties of human erythrocyte glutathione peroxidase. J Biol Chem. 1975 Jul 10;250(13):5144–5149. [PubMed] [Google Scholar]
- Bachur N. R., Gordon S. L., Gee M. V. A general mechanism for microsomal activation of quinone anticancer agents to free radicals. Cancer Res. 1978 Jun;38(6):1745–1750. [PubMed] [Google Scholar]
- Bachur N. R., Gordon S. L., Gee M. V. Anthracycline antibiotic augmentation of microsomal electron transport and free radical formation. Mol Pharmacol. 1977 Sep;13(5):901–910. [PubMed] [Google Scholar]
- Bachur N. R., Hildebrand R. C., Jaenke R. S. Adriamycin and daunorubicin disposition in the rabbit. J Pharmacol Exp Ther. 1974 Nov;191(2):331–340. [PubMed] [Google Scholar]
- Beckman G., Lundgren E., Tärnvik A. Superoxide dismutase isozymes in different human tissues, their genetic control and intracellular localization. Hum Hered. 1973 Apr;23(4):338–345. doi: 10.1159/000152594. [DOI] [PubMed] [Google Scholar]
- Benjamin R. S., Riggs C. E., Jr, Bachur N. R. Plasma pharmacokinetics of adriamycin and its metabolites in humans with normal hepatic and renal function. Cancer Res. 1977 May;37(5):1416–1420. [PubMed] [Google Scholar]
- Burk R. F., Nishiki K., Lawrence R. A., Chance B. Peroxide removal by selenium-dependent and selenium-independent glutathione peroxidases in hemoglobin-free perfused rat liver. J Biol Chem. 1978 Jan 10;253(1):43–46. [PubMed] [Google Scholar]
- Carter S. K. Adriamycin-a review. J Natl Cancer Inst. 1975 Dec;55(6):1265–1274. doi: 10.1093/jnci/55.6.1265. [DOI] [PubMed] [Google Scholar]
- Chio K. S., Tappel A. L. Inactivation of ribonuclease and other enzymes by peroxidizing lipids and by malonaldehyde. Biochemistry. 1969 Jul;8(7):2827–2832. doi: 10.1021/bi00835a020. [DOI] [PubMed] [Google Scholar]
- Cohen G., Dembiec D., Marcus J. Measurement of catalase activity in tissue extracts. Anal Biochem. 1970 Mar;34:30–38. doi: 10.1016/0003-2697(70)90083-7. [DOI] [PubMed] [Google Scholar]
- Del Río L. A., Ortega M. G., López A. L., Gorgé J. L. A more sensitive modification of the catalase assay with the Clark oxygen electrode. Application to the kinetic study of the pea leaf enzyme. Anal Biochem. 1977 Jun;80(2):409–415. doi: 10.1016/0003-2697(77)90662-5. [DOI] [PubMed] [Google Scholar]
- Diplock A. T., Baum H., Lucy J. A. The effect of vitamin E on the oxidation state of selenium in rat liver. Biochem J. 1971 Aug;123(5):721–729. doi: 10.1042/bj1230721. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Donelli M. G., Martini A., Colombo T., Bossi A., Garattini S. Heart levels of adriamycin in normal and tumor-bearing mice. Eur J Cancer. 1976 Nov;12(11):913–923. doi: 10.1016/0014-2964(76)90009-8. [DOI] [PubMed] [Google Scholar]
- Fridovich I. The biology of oxygen radicals. Science. 1978 Sep 8;201(4359):875–880. doi: 10.1126/science.210504. [DOI] [PubMed] [Google Scholar]
- Goodman J., Hochstein P. Generation of free radicals and lipid peroxidation by redox cycling of adriamycin and daunomycin. Biochem Biophys Res Commun. 1977 Jul 25;77(2):797–803. doi: 10.1016/s0006-291x(77)80048-x. [DOI] [PubMed] [Google Scholar]
- Keele B. B., Jr, McCord J. M., Fridovich I. Further characterization of bovine superoxide dismutase and its isolation from bovine heart. J Biol Chem. 1971 May 10;246(9):2875–2880. [PubMed] [Google Scholar]
- LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
- Lawrence R. A., Burk R. F. Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Commun. 1976 Aug 23;71(4):952–958. doi: 10.1016/0006-291x(76)90747-6. [DOI] [PubMed] [Google Scholar]
- Lenaz L., Page J. A. Cardiotoxicity of adriamycin and related anthracyclines. Cancer Treat Rev. 1976 Sep;3(3):111–120. doi: 10.1016/s0305-7372(76)80018-7. [DOI] [PubMed] [Google Scholar]
- Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep. 1966 Mar;50(3):163–170. [PubMed] [Google Scholar]
- Maral J., Puget K., Michelson A. M. Comparative study of superoxide dismutase, catalase and glutathione peroxidase levels in erythrocytes of different animals. Biochem Biophys Res Commun. 1977 Aug 22;77(4):1525–1535. doi: 10.1016/s0006-291x(77)80151-4. [DOI] [PubMed] [Google Scholar]
- Marcus A. J., Silk S. T., Safier L. B., Ullman H. L. Superoxide production and reducing activity in human platelets. J Clin Invest. 1977 Jan;59(1):149–158. doi: 10.1172/JCI108613. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McCord J. M., Fridovich I. Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem. 1969 Nov 25;244(22):6049–6055. [PubMed] [Google Scholar]
- McCray P. B., Gibson D. D., Fong K. L., Hornbrook K. R. Effect of glutathione peroxidase activity on lipid peroxidation in biological membranes. Biochim Biophys Acta. 1976 Jun 22;431(3):459–468. [PubMed] [Google Scholar]
- Misra H. P., Fridovich I. The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem. 1972 May 25;247(10):3170–3175. [PubMed] [Google Scholar]
- Myers C. E., McGuire W. P., Liss R. H., Ifrim I., Grotzinger K., Young R. C. Adriamycin: the role of lipid peroxidation in cardiac toxicity and tumor response. Science. 1977 Jul 8;197(4299):165–167. doi: 10.1126/science.877547. [DOI] [PubMed] [Google Scholar]
- Omaye S. T., Reddy K. A., Cross C. E. Enhanced lung toxicity of paraquat in selenium-deficient rats. Toxicol Appl Pharmacol. 1978 Feb;43(2):237–247. doi: 10.1016/0041-008x(78)90003-0. [DOI] [PubMed] [Google Scholar]
- Oshino N., Chance B. Properties of glutathione release observed during reduction of organic hydroperoxide, demethylation of aminopyrine and oxidation of some substances in perfused rat liver, and their implications for the physiological function of catalase. Biochem J. 1977 Mar 15;162(3):509–525. doi: 10.1042/bj1620509. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Paglia D. E., Valentine W. N. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med. 1967 Jul;70(1):158–169. [PubMed] [Google Scholar]
- Rister M., Baehner R. L. The alteration of superoxide dismutase, catalase, glutathione peroxidase, and NAD(P)H cytochrome c reductase in guinea pig polymorphonuclear leukocytes and alveolar macrophages during hyperoxia. J Clin Invest. 1976 Nov;58(5):1174–1184. doi: 10.1172/JCI108570. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rotruck J. T., Pope A. L., Ganther H. E., Hoekstra W. G. Prevention of oxidative damage to rat erythrocytes by dietary selenium. J Nutr. 1972 May;102(5):689–696. doi: 10.1093/jn/102.5.689. [DOI] [PubMed] [Google Scholar]
- Schwartz H. S. A fluorometric assay for daunomycin and adriamycin in animal tissues. Biochem Med. 1973 Jun;7(3):396–404. doi: 10.1016/0006-2944(73)90060-4. [DOI] [PubMed] [Google Scholar]
- Sonneveld P. Effect of alpha-tocopherol on the cardiotoxicity of adriamycin in the rat. Cancer Treat Rep. 1978 Jul;62(7):1033–1036. [PubMed] [Google Scholar]
- Stevens J. B., Autor A. P. Induction of superoxide dismutase by oxygen in neonatal rat lung. J Biol Chem. 1977 May 25;252(10):3509–3514. [PubMed] [Google Scholar]
- Thayer W. S. Adriamycin stimulated superoxide formation in submitochondrial particles. Chem Biol Interact. 1977 Dec;19(3):265–278. doi: 10.1016/0009-2797(77)90050-3. [DOI] [PubMed] [Google Scholar]
- Van Vleet J. F., Greenwood L., Ferrans V. J., Rebar A. H. Effect of selenium-vitamin E on adriamycin-induced cardiomyopathy in rabbits. Am J Vet Res. 1978 Jun;39(6):997–1010. [PubMed] [Google Scholar]
- WILLS E. D. Effect of unsaturated fatty acids and their peroxides on enzymes. Biochem Pharmacol. 1961 Jul;7:7–16. doi: 10.1016/0006-2952(61)90119-8. [DOI] [PubMed] [Google Scholar]
- Wang J. J., Chervinsky D. S., Rosen J. M. Comparative biochemical studies of adriamycin and daunomycin in leukemic cells. Cancer Res. 1972 Mar;32(3):511–515. [PubMed] [Google Scholar]