Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1984 Jul;81(13):4198–4202. doi: 10.1073/pnas.81.13.4198

Cholesterol epoxide is a direct-acting mutagen.

A Sevanian, A R Peterson
PMCID: PMC345396  PMID: 6588383

Abstract

A 24-hr treatment of V79 Chinese hamster lung fibroblasts with 12.4 microM cholesterol 5 alpha, 6 alpha-epoxide induced 8-azaguanine-resistant mutants at frequencies 4.6- to 11.8-fold higher than the spontaneous mutation rate. We show that cholesterol epoxide, which is produced by in vivo cholesterol oxidation, is a weak direct-acting mutagen. Cholesterol epoxide was found to be accumulated by cells and transformed to cholestane-3 beta, 5 alpha, 6 beta-triol, which was more toxic and a more potent inhibitor of DNA synthesis than the epoxide but, at concentrations less than 17.8 microM, was not significantly mutagenic. Consideration of the rates of cholesterol epoxide conversion to cholestane triol shows that this conversion can result in abolition of the mutagenicity of the epoxide. Conditions under which conversion of the epoxide to the triol is low, as in the case of low epoxide hydrolase activity, favor mutagenicity whereas rapid conversion to triol favors cytotoxicity.

Full text

PDF
4198

Selected References

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

  1. Aringer L., Eneroth P. Formation and metabolism in vitro of 5,6-epoxides of cholesterol and beta-sitosterol. J Lipid Res. 1974 Jul;15(4):389–398. [PubMed] [Google Scholar]
  2. Barnes D., Wiesner K. Polarographic determination of the reaction rate of the second step in an SN1 displacement. Experientia. 1971 Dec 15;27(12):1379–1380. doi: 10.1007/BF02154238. [DOI] [PubMed] [Google Scholar]
  3. Bischoff F. Carcinogenic effects of steroids. Adv Lipid Res. 1969;7:165–244. doi: 10.1016/b978-0-12-024907-7.50011-7. [DOI] [PubMed] [Google Scholar]
  4. Black H. S. Analysis and physiologic significance of cholesterol epoxide in animal tissues. Lipids. 1980 Sep;15(9):705–709. doi: 10.1007/BF02534024. [DOI] [PubMed] [Google Scholar]
  5. Black H. S., Chan J. T. Etiologic related studies of ultraviolet light-mediated carcinogenesis. Oncology. 1976;33(3):119–122. doi: 10.1159/000225124. [DOI] [PubMed] [Google Scholar]
  6. Black H. S., Douglas D. R. A model system for the evaluation of the role of cholesterol -oxide in ultraviolet carcinogenesis. Cancer Res. 1972 Dec;32(12):2630–2632. [PubMed] [Google Scholar]
  7. Bowden J. P., Muschik G. M., Kawalek J. C. The metabolic fate of cholesterol-5 alpha, 6 alpha-expoxide in vivo. Lipids. 1979 Jul;14(7):623–629. doi: 10.1007/BF02533447. [DOI] [PubMed] [Google Scholar]
  8. Fioriti J. A., Kanuk M. J., George M., Sims R. J. Metabolic fate of epoxycholesterol in the rat. Lipids. 1970 Jan;5(1):71–75. doi: 10.1007/BF02531097. [DOI] [PubMed] [Google Scholar]
  9. Gray M. F., Lawrie T. D., Brooks C. J. Isolation and identification of cholesterol -oxide and other minor sterols in human serum. Lipids. 1971 Nov;6(11):836–843. doi: 10.1007/BF02531214. [DOI] [PubMed] [Google Scholar]
  10. Hayakawa T., Lemahieu R. A., Udenfriend S. Studies on glutathione-S-arene oxidase transferase. A sensitive assay and partial purification of the enzyme from sheep liver. Arch Biochem Biophys. 1974 May;162(1):223–230. doi: 10.1016/0003-9861(74)90122-2. [DOI] [PubMed] [Google Scholar]
  11. Imai H., Werthessen N. T., Subramanyam V., LeQuesne P. W., Soloway A. H., Kanisawa M. Angiotoxicity of oxygenated sterols and possible precursors. Science. 1980 Feb 8;207(4431):651–653. doi: 10.1126/science.7352277. [DOI] [PubMed] [Google Scholar]
  12. Kadis B. Steroid epoxides in biologic systems: a review. J Steroid Biochem. 1978 Jan;9(1):75–81. doi: 10.1016/0022-4731(78)90105-x. [DOI] [PubMed] [Google Scholar]
  13. Kelsey M. I., Pienta R. J. Transformation of hamster embryo cells by cholesterol-alpha-epoxide and lithocholic acid. Cancer Lett. 1979 Mar;6(3):143–149. doi: 10.1016/s0304-3835(79)80025-7. [DOI] [PubMed] [Google Scholar]
  14. Kelsey M. I., Pienta R. J. Transformation of hamster embryo cells by neutral sterols and bile acids. Toxicol Lett. 1981 Oct;9(2):177–182. doi: 10.1016/0378-4274(81)90037-0. [DOI] [PubMed] [Google Scholar]
  15. Painter R. B., Howard R. A comparison of the HeLa DNA-synthesis inhibition test and the Ames test for screening of mutagenic carcinogens. Mutat Res. 1978 Aug;54(1):113–115. doi: 10.1016/0165-1161(78)90142-5. [DOI] [PubMed] [Google Scholar]
  16. Painter R. B., Howard R. The Hela DNA-synthesis inhibition test as a rapid screen for mutagenic carcinogens. Mutat Res. 1982 Feb 22;92(1-2):427–437. doi: 10.1016/0027-5107(82)90241-x. [DOI] [PubMed] [Google Scholar]
  17. Parsons P. G., Goss P. Chromosome damage and DNA repair induced in human fibroblasts by UV and cholesterol oxide. Aust J Exp Biol Med Sci. 1978 Jun;56(3):287–296. doi: 10.1038/icb.1978.30. [DOI] [PubMed] [Google Scholar]
  18. Peterson A. R. DNA synthesis, mutagenesis, DNA damage, and cytotoxicity in cultured mammalian cells treated with alkylating agents. Cancer Res. 1980 Mar;40(3):682–688. [PubMed] [Google Scholar]
  19. Peterson A. R., Peterson H., Heidelberger C. Oncogenesis, mutagenesis, DNA damage, and cytotoxicity in cultured mammalian cells treated with alkylating agents. Cancer Res. 1979 Jan;39(1):131–138. [PubMed] [Google Scholar]
  20. Petrakis N. L., Gruenke L. D., Craig J. C. Cholesterol and cholesterol epoxides in nipple aspirates of human breast fluid. Cancer Res. 1981 Jun;41(6):2563–2565. [PubMed] [Google Scholar]
  21. Raicht R. F., Cohen B. I. Sterol metabolism in the rat. Effect of cholesterol and cholesterol-alpha-epoxide on sterol metabolism in rats fed liquid diets. Biochim Biophys Acta. 1981 Dec 23;666(3):455–461. doi: 10.1016/0005-2760(81)90306-4. [DOI] [PubMed] [Google Scholar]
  22. Reddy B. S., Watanabe K. Effect of cholesterol metabolites and promoting effect of lithocholic acid in colon carcinogenesis in germ-free and conventional F344 rats. Cancer Res. 1979 May;39(5):1521–1524. [PubMed] [Google Scholar]
  23. Reddy B. S., Wynder E. L. Metabolic epidemiology of colon cancer. Fecal bile acids and neutral sterols in colon cancer patients and patients with adenomatous polyps. Cancer. 1977 Jun;39(6):2533–2539. doi: 10.1002/1097-0142(197706)39:6<2533::aid-cncr2820390634>3.0.co;2-x. [DOI] [PubMed] [Google Scholar]
  24. Roscoe H. G., Fahrenbach M. J. Metabolism of cholestane-3 beta,5 alpha,6 beta-triol. II. Identification of two major neutral metabolites in the rat. J Lipid Res. 1971 Jan;12(1):17–23. [PubMed] [Google Scholar]
  25. Sevanian A., Mead J. F., Stein R. A. Epoxides as products of lipid autoxidation in rat lungs. Lipids. 1979 Jul;14(7):634–643. doi: 10.1007/BF02533449. [DOI] [PubMed] [Google Scholar]
  26. Sevanian A., Stein R. A., Mead J. F. Lipid epoxide hydrolase in rat lung preparations. Biochim Biophys Acta. 1980 Aug 7;614(2):489–500. doi: 10.1016/0005-2744(80)90238-7. [DOI] [PubMed] [Google Scholar]
  27. Smith L. L., Smart V. B., Ansari G. A. Mutagenic cholesterol preparations. Mutat Res. 1979 Sep;68(1):23–30. doi: 10.1016/0165-1218(79)90074-0. [DOI] [PubMed] [Google Scholar]
  28. Watabe T., Kanai M., Isobe M., Ozawa N. Cholesterol alpha- and beta-epoxides as obligatory intermediates in the hepatic microsomal metabolism of cholesterol to cholestanetriol. Biochim Biophys Acta. 1980 Aug 11;619(2):414–419. doi: 10.1016/0005-2760(80)90090-9. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES