4-Hydroxylated metabolites of the antiestrogens tamoxifen and toremifene are metabolized to unusually stable quinone methides

Chemical Research in Toxicology

Volumn 13, Issue 1, 2000, Pages 45-52

  Fan, Peter W ^a   Zhang, Fagen ^a   Bolton, Judy L ^a  

^a UNIVERSITY OF ILLINOIS AT CHICAGO   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 HYDROXYTAMOXIFEN; 4 HYDROXYTOREMIFENE; EPISULFONIUM; GLUTATHIONE; QUINONE DERIVATIVE; TAMOXIFEN; TOREMIFENE; UNCLASSIFIED DRUG;

AEROBIC METABOLISM; ANIMAL CELL; ARTICLE; CARCINOGENICITY; DNA ALKYLATION; DRUG CYTOTOXICITY; DRUG HALF LIFE; DRUG METABOLISM; DRUG STRUCTURE; FEMALE; GENOTOXICITY; HUMAN; HUMAN CELL; NONHUMAN; RAT;

ANIMALS; ANTINEOPLASTIC AGENTS, HORMONAL; BREAST NEOPLASMS; CYTOCHROME P-450 ENZYME SYSTEM; ESTROGEN RECEPTOR MODULATORS; FEMALE; GLUTATHIONE; HUMANS; HYDROXYLATION; INDOLEQUINONES; INDOLES; MASS SPECTROMETRY; OXIDATION-REDUCTION; QUINONES; RATS; RATS, SPRAGUE-DAWLEY; TAMOXIFEN; TOREMIFENE; TUMOR CELLS, CULTURED;

ANIMALIA; MINK CELL FOCUS-FORMING VIRUS;

EID: 0033958868     PISSN: 0893228X     EISSN: None     Source Type: Journal    
DOI: 10.1021/tx990144v     Document Type: Article

References (54)

1. Magriples, U., Naftolin, F., Schwartz, P. E., and Carcangiu, M. L. (1993) High-grade endometrial carcinoma in tamoxifen-treated breast cancer patients. J. Clin. Oncol. 11, 485-490.
2. Seoud, M. A., Johnson, J., and Weed, J. C., Jr. (1993) Gynecologic tumors in tamoxifen-treated women with breast cancer. Obstet. Gynecol. 82, 165-169.
3. Fisher, B., Constantino, J. P., Redmond, C. K., Fisher, E. R., Wickerham, D. L., and Cronin, W. M. (1994) Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel project (NSABP) B-14. J. Natl. Cancer Inst. 86, 527-537.
4. van Leeuwen, F. E., Benraadt, J., Coebergh, J. W., Kiemeney, L. A., Gimbrere, C. H., Otter, R., Schouten, L. J., Damhuis, R. A., Bontenbal, M., Diepenhorst, F. W., van den Belt-Dusebout, A. W., and van Tinteren, H. (1994) Risk of endometrial cancer after tamoxifen treatment of breast cancer. Lancet 343, 448-452.
5. Cook, L. S., Weiss, N. S., Schwartz, S. M., White, E., McKnight, B., Moore, D. E., and Daling, J. R. (1995) Population-based study of tamoxifen therapy and subsequent ovarian, endometrial, and breast cancers. J. Natl. Cancer Inst. 87, 1359-1364.
6. Cuenca, R. E., Giachino, J., Arredondo, M. A., Hempling, R., and Edge, S. B. (1996) Endometrial carcinoma associated with breast carcinoma: low incidence with tamoxifen use. Cancer 77, 2058-2063.
7. Curtis, R. E., Boice, J. D., Jr., Shriner, D. A., Hankey, B. F., and Fraumeni, J. F., Jr. (1996) Second cancers after adjuvant tamoxifen therapy for breast cancer. J. Natl. Cancer Inst. 88, 832-834.
8. White, I. N. H., de Matteis, F., Davies, A., Smith, L. L., Crofton-Sleigh, C., Venitt, S., Hewwe, A., and Phillips, D. H. (1992) Genotoxic potential of tamoxifen and analogues in female Fischer F344/n rats, DBA/2 and C57B1/6 mice and in human MCL-5 cells. Carcinogenesis 13, 2197-2203.
9. Han, X., and Liehr, J. G. (1992) Induction of covalent DNA adducts in rodents by tamoxifen. Cancer Res. 52, 1360-1363.
10. 32P-postlabeling and use of metabolic inhibitors for two distinct pathways leading to mouse hepatic DNA adduct formation and identification of 4-hydroxytamoxifen as a proximate metabolite. Carcinogenesis 15, 2087-2094.
11. Greaves, P., Goonetilleke, R., Nunn, G., Topham, J., and Orton, T. (1993) Two-year carcinogenicity study of tamoxifen in Alderley Park-Wistar derived rats. Cancer Res. 53, 3919-3924.
12. Williams, G. M., Iatropoulos, M. J., and Karlsson, S. (1997) Initiating activity of the anti-estrogen tamoxifen, but not toremifene in rat-liver. Carcinogenesis 18, 2247-2253.
13. Carthew, P., Nolan, B. M., Edwards, R. E., and Smith, L. L. (1996) The role of cell death and cell proliferation in the promotion of rat liver tumors by tamoxifen. Cancer Lett. 106, 163-169.
14. IARC Monograph on the Evaluation of the Carcinogenic Risks of Chemicals to Humans: Some Pharmaceutical Drugs (1996) Vol. 66, pp 253-365, International Agency for Research on Cancer, Lyon, France.
15. Hardcastle, I. R., Horton, M. N., Osborne, M. R., Hewer, A., Jarman, M., and Phillips, D. H. (1998) Synthesis and DNA reactivity of α-hydroxylated metabolites of nonsteroidal antiestrogens. Chem. Res. Toxicol. 11, 369-374.
16. Shibutani, S., Dasaradhi, L., Terashima, I., Banoglu, E., and Duffel, M. W. (1998) α-Hydroxytamoxifen is a substrate of hydroxysteroid (alcohol) sulfotransferase, resulting in tamoxifen DNA adducts. Cancer Res. 58, 647-653.
17. Dasaradhi, L., and Shibutani, S. (1997) Identification of tamoxifen-DNA adducts formed by α-sulfate tamoxifen and α-acetoxytamoxifen. Chem. Res. Toxicol. 10, 189-196.
18. Dehal, S. S., and Kupfer, D. (1996) Evidence that the catechol 3,4-dihydroxytamoxifen is a proximate intermediate to the reactive species binding covalently to proteins. Cancer Res. 56, 1283-1290.
19. Dehal, S. S., and Kupfer, D. (1999) Cytochrome P-450 3A and 2D6 catalyze ortho hydroxylation of 4-hydroxytamoxifen and 3-hydroxytamoxifen (Droloxifene) yielding tamoxifen catechol: involvement of catechols in covalent binding to hepatic proteins. Drug Metab. Dispos. 27, 681-688.
20. Beland, F. A., McDaniel, L. P., and Marques, M. M. (1999) Comparison of the DNA adducts formed by tamoxifen and 4-hydroxytamoxifen in vivo. Carcinogenesis 20, 471-477.
21. Osborne, M. R., Davis, W., Hewer, A. J., Hardcastle, I. R., and Phillips, D. H. (1999) 4-Hydroxytamoxifen gives DNA adducts by chemical activation, but not in rat liver cells. Chem. Res. Toxicol. 12, 151-158.
22. Marques, M. M., and Beland, F. A. (1997) Identification of tamoxifen-DNA adducts formed by 4-hydroxytamoxifen quinone methide. Carcinogenesis 18, 1949-1954.
23. Potter, G. A., McCague, R., and Jarman, M. (1994) A mechanistic hypothesis for DNA adduct formation by tamoxifen following hepatic oxidative metabolism. Carcinogenesis 15, 439-442.
24. Kuramochi, H. (1996) Conformational studies and electronic structures of tamoxifen and toremifene and their allylic carbocations proposed as reactive intermediates leading to DNA adduct formation. J. Med. Chem. 39, 2877-2886.
25. Thompson, D. C., Perera, K., Krol, E. S., and Bolton, J. L. (1995) o-Methoxy-4-alkylphenols that form quinone methides of intermediate reactivity are the most toxic in rat liver slices. Chem. Res. Toxicol. 8, 323-327.
26. Bolton, J. L., Valerio, L. G. J., and Thompson, J. A. (1992) The enzymatic formation and chemical reactivity of quinone methides correlate with alkylphenol-induced toxicity in rat hepatocytes. Chem. Res. Toxicol. 5, 816-822.
27. Valavaara, R., Pyrrhonen, S., Heikkinen, M., Rissanen, P., Blanco, G., Tholix, E., Nordman, E., Taskinen, P., Holsti, L., and Hajba, A. (1988) Toremifene, a new antiestrogenic compound, for treatment of advanced breast cancer. Phase II study. Eur. J. Cancer Clin. Oncol. 24, 785-790.
28. Simberg, N. H., Murai, J. T., and Siiteri, P. K. (1990) In vitro and in vivo binding of toremifene and its metabolites in rat uterus. J. Steroid Biochem. 36, 197-202.
29. Sipila, H., Kangas, L., Vourilehto, L., Kalapudas, A., Eloranta, M., Soderwall, M., Toivala, R., and Anttila, M. (1990) Metabolism of toremifene in the rat. J. Steroid Biochem. 36, 211-215.
30. NIH Guidelines for the Laboratory Use of Chemical Carcinogens, NIH Publication 81-2385 (1981) U.S. Government Printing Office, Washington, DC.
31. Gauthier, S., Mailhot, J., and Labrie, F. (1996) New highly stereoselective synthesis of (Z)-4-hydroxytamoxifen and of (Z)-4-hydroxytoremifene via McMurry reaction. J. Org. Chem. 61, 3890-3893.
32. Thompson, J. A., Malkinson, A. M., Wand, M. D., Mastovich, S. L., Mead, E. W., Schullek, K. M., and Laudenschlager, W. G. (1987) Oxidative metabolism of butylated hydroxytoluene by hepatic and pulmonary microsomes from rats and mice. Drug Metab. Dispos. 15, 833-840.
33. Liehr, J. G., DaGue, B. B., Ballatore, A. M., and Hankin, J. (1983) Diethylstilbestrol (DES) quinone: a reactive intermediates in DES metabolism. Biochem. Pharmacol. 32, 3711-3781.
34. Filar, L. J., and Winstein, S. (1960) Preparation and behavior of simple quinone methides. Tetrahedron Lett. 25, 9-16.
35. Bolton, J. L., Comeau, E., and Vukomanovic, V. (1995) The influence of 4-alkyl substituents on the formation and reactivity of 2-methoxy-quinone methides: Evidence that extended π-conjugation dramatically stabilizes the quinone methide formed from eugenol. Chem.-Biol. Interact. 95, 279-290.
36. Dwivedy, I., Devanesan, P., Cremonesi, P., Rogan, E., and Cavalieri, E. (1992) Synthesis and characterization of estrogen 2,3-and 3,4-quinones. Comparison of DNA adducts formed by the quinones versus horseradish peroxidase-activated catechol estrogens. Chem. Res. Toxicol. 5, 828-833.
37. Peter, M. G. (1989) Chemical modifications of biopolymers by quinones and quinone methides. Angew. Chem., Int. Ed. 28, 555-570.
38. Thompson, D. C., Thompson, J. A., Sugumaran, M., and Moldeus, P. (1993) Biological and toxicological consequences of quinone methide formation. Chem.-Biol. Interact. 86, 129-162.
39. Powis, G. (1987) Metabolism and reactions of quinoid anticancer agents. Pharmacol. Ther. 35, 57-162.
40. Erve, J. C. L., Barofsky, E., Barofsky, D. F., Deinzer, M. L., and Reed, D. (1995) Alkylation of Escherichia coli thioredoxin by S-(2-chloroehtyl)glutathione and identification of the adduct on the active site cysteine-32 by mass spectrometry. Chem. Res. Toxicol. 8, 934-941.
41. Erve, J. C., Deinzer, M. L., and Reed, D. J. (1995) Alkylation of oxytocin by S-(2-chloroethyl)glutathione and characterization of adducts by tandem mass spectrometry and Edman degradation. Chem. Res. Toxicol. 8, 414-421.
42. Soderlund, E. J., Meyer, D. J., Ketterer, B., Nelson, S. D., Dybing, E., and Holme, J. A. (1995) Metabolism of 1,2-dibromo-3-chloropropane by glutathione S-transferases. Chem.-Biol. Interact. 97, 257-272.
43. Thier, R., Muller, M., Taylor, J. B., Pemble, S. E., Ketterer, B., and Guengerich, F. P. (1995) Enhancement of bacterial mutagenicity of bifunctional alkylating agents by expression of mammalian glutathione S-transferase. Chem. Res. Toxicol. 8, 465-472.
44. Weber, G., Steenwyk, R. C., Nelson, S. D., and Pearson, P. G. (1995) Identification of N-acetylcysteine conjugates of 1,2-dibromo-3-chloropropane: evidence for cytochrome P450 and glutathione mediated bioactivation pathways. Chem. Res. Toxicol. 8, 560-573.
45. Erve, J. C. L., Deinzer, M. L., and Reed, D. J. (1996) Reaction of human hemoglobin toward the alkylating agent S-(2-chloroethyl)-glutathione. J. Toxicol. Environ. Health 49, 127-143.
46. 6-guanyl)ethyl]glutathione at a single site. Chem. Res. Toxicol. 10, 1133-1143.
47. Kassahun, K., Davis, M., Hu, P., Martin, B., and Baillie, T. (1997) Biotransformation of the naturally occurring isothiocyanate sulforaphane in the rat: Identification of phase I metabolites and glutathione conjugates. Chem. Res. Toxicol. 10, 1228-1233.
48. Ramanathan, R., Cao, K., Cavalieri, E., and Gross, M. L. (1998) Mass spectrometric methods for distinguishing structural isomers of glutathione conjugates of estrone and estradiol. J. Am. Soc. Mass Spectrom. 6, 612-619.
49. Cao, K., Stack, D. E., Ramanathan, R., Gross, M. L., Rogan, E. G., and Cavalieri, E. L. (1998) Synthesis and structure elucidation of estrogen quinones conjugated with cysteine, N-acetylcysteine, and glutathione. Chem. Res. Toxicol. 11, 909-916.
50. Crewe, H. K., Ellis, S. W., Lennard, M. S., and Tucker, G. T. (1997) Variable contribution of cytochromes P450 2D6, 2C9 and 3A4 to the 4-hydroxylation of tamoxifen by human liver microsomes. Biochem. Pharmacol. 53, 171-178.
51. Bolton, J. L., Turnipseed, S. B., and Thompson, J. A. (1997) Influence of quinone methide reactivity on the alkylation of thiol and amino groups in proteins: studies utilizing amino acid and peptide models. Chem.-Biol. Interact. 107, 185-200.
52. Reed, M., and Thompson, D. C. (1997) Immunochemical visualization and identification of rat liver proteins adducted by 2,6-ditert-butyl-4-methylphenol (BHT). Chem. Res. Toxicol. 10, 1109-1117.
53. Nakagawa, Y., Hiraga, K., and Suga, T. (1983) On the mechanism of covalent binding of butylated hydroxytoluene to microsomal protein. Biochem. Pharmacol. 15, 1417-1421.
54. Zhang, F., Fan, P. W., Liu, X., Shen, L., van Breemen, R., and Bolton, J. L. (2000) Synthesis and reactivity of a potential carcinogenic metabolite of tamoxifen: 3,4-Dihydroxytamoxifen-o-quinone. Chem. Res. Toxicol. 13, 53-62.