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Characterization of the Human Cytochrome P450 Forms Involved in Metabolism of Tamoxifen to Its α-Hydroxy and α,4-Dihydroxy Derivatives

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School of Biomedical Sciences, University of Queensland, St. Lucia, Australia 4072, Academic Unit of Clinical Pharmacology, Division of Clinical Sciences South, University of Sheffield, Royal Hallamshire Hospital, Sheffield S10 2JF, United Kingdom, and Department of Medicine, University of Queensland and Department of Clinical Pharmacology, Princess Alexandra Hospital, Woolloongabba 4102, Australia
Cite this: Chem. Res. Toxicol. 2005, 18, 10, 1611–1618
Publication Date (Web):September 30, 2005
Copyright © 2005 American Chemical Society

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    Tamoxifen is a known hepatocarcinogen in rats and is associated with an increased incidence of endometrial cancer in patients. One mechanism for these actions is via bioactivation, where reactive metabolites are generated that are capable of binding to DNA or protein. Several metabolites of tamoxifen have been identified that appear to predispose to adduct formation. These include α-hydroxytamoxifen, α,4-dihydroxytamoxifen, and α-hydroxy-N-desmethyltamoxifen. Previous studies have shown that cytochrome P450 (P450) enzymes play an important role in the biotransformation of tamoxifen. The aim of our work was to determine which P450 enzymes were capable of producing α-hydroxylated metabolites from tamoxifen. When tamoxifen (18 or 250 μM) was used as the substrate, P450 3A4, and to a lesser extent, P450 2D6, P450 2B6, P450 3A5, P450 2C9, and P450 2C19 all produced a metabolite with the same HPLC retention time as α-hydroxytamoxifen at either substrate concentration tested. This peak was well-separated from 4-hydroxy-N-desmethyltamoxifen, which eluted substantially later under the chromatographic conditions used. No α,4-dihydroxytamoxifen was detected in incubations with any of the forms with tamoxifen as substrate. However, when 4-hydroxytamoxifen (100 μM) was used as the substrate, P450 2B6, P450 3A4, P450 3A5, P450 1B1, P450 1A1, and P450 2D6 all produced detectable concentrations of α,4-dihydroxytamoxifen. These studies demonstrate that multiple human P450s, including forms found in the endometrium, may generate reactive metabolites in women undergoing tamoxifen therapy, which could subsequently play a role in the development of endometrial cancer.

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     University of Queensland.

     Royal Hallamshire Hospital.


     Princess Alexandra Hospital.


     To whom correspondence should be addressed. (M.S.L.) Tel:  +44-114-271 2578. Fax:  +44-114-272 0275. E-mail:  M.S.Lennard@ (E.M.J.) Tel:  +61-7-3365 1410. Fax:  +61-7-3365 1766. E-mail:  [email protected].

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    8. Jin-Ryul Hu, Tae-Woo Jang, Su-Jin Kang, Sae-Kwang Ku, Seong-Hun Choi, Young-Joon Lee. Effects of mixed formulation of tamoxifen and blue honeysuckle on the pharmacokinetics profiles of tamoxifen after single oral administration. Journal of Korean Medicine 2019, 40 (4) , 1-15.
    9. A.B. Sanchez-Spitman, J.J. Swen, V.O. Dezentje, D.J.A.R. Moes, H. Gelderblom, H.J. Guchelaar. Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen. Expert Review of Clinical Pharmacology 2019, 12 (6) , 523-536.
    10. Eun-A Ryu, 송창현, 최성훈, 한창현, 이영준, 구세광, 강수진, Bong Hyo Lee. Effect of Gamiondam-tang (GMODT), a Polyherbal Formula on the Pharmacokinetics Profiles of Tamoxifen in Male SD Rats (2) - Single Oral Combination Treatment of Tamoxifen 50 mg/kg with GMODT 100 mg/kg with 2.5 hr-intervals -. Society of Preventive Korean Medicine 2017, 21 (2) , 127-137.
    11. Eun-A Ryu, Su-Jin Kang, Chang-Hyun Song, Bong-Hyo Lee, Seong-Hun Choi, Chang-Hyun Han, Young-Joon Lee, Sae-Kwang Ku. Effect of (GMODT), a Polyherbal Formula on the Pharmacokinetics Profiles of Tamoxifen in Male SD Rats. Journal of Korean Medicine 2017, 38 (2) , 61-72.
    12. Doshi Utkarsh, Carol Loretz, Albert P. Li. In vitro evaluation of hepatotoxic drugs in human hepatocytes from multiple donors: Identification of P450 activity as a potential risk factor for drug-induced liver injuries. Chemico-Biological Interactions 2016, 255 , 12-22.
    13. Min A Kwak, Soo Jin Park, Sung Hwan Park, Young Joon Lee, Sae Kwang Ku. Effect of Jaeumkanghwatang (JEKHT), a Polyherbal Formula on the Pharmacokinetics Profiles of Tamoxifen in Male SD Rats (1) - Single Oral Combination Treatment of Tamoxifen 50 mg/kg with JEKHT 100 mg/kg within 5 min -. Journal of Korean Medicine 2016, 37 (2) , 1-11.
    14. Marie‐Aude Richard, Didier Hamels, Pascal Pigeon, Siden Top, Patrick M. Dansette, Hui Zhi Shirley Lee, Anne Vessières, Daniel Mansuy, Gérard Jaouen. Oxidative Metabolism of Ferrocene Analogues of Tamoxifen: Characterization and Antiproliferative Activities of the Metabolites. ChemMedChem 2015, 10 (6) , 981-990.
    15. F. Peter Guengerich. Human Cytochrome P450 Enzymes. 2015, 523-785.
    16. Lynn H. Pottenger, Larry S. Andrews, Ammie N. Bachman, Peter J. Boogaard, Jean Cadet, Michelle R. Embry, Peter B. Farmer, Matthew W. Himmelstein, Annie M. Jarabek, Elizabeth A. Martin, Robert J. Mauthe, Rudranath Persaud, R. Julian Preston, Rita Schoeny, Julie Skare, James A. Swenberg, Gary M. Williams, Errol Zeiger, Fagen Zhang, James H. Kim. An organizational approach for the assessment of DNA adduct data in risk assessment: case studies for aflatoxin B 1 , tamoxifen and vinyl chloride. Critical Reviews in Toxicology 2014, 44 (4) , 348-391.
    17. Monika Pawłowska, Ewa Augustin, Zofia Mazerska. CYP3A4 overexpression enhances apoptosis induced by anticancer agent imidazoacridinone C-1311, but does not change the metabolism of C-1311 in CHO cells. Acta Pharmacologica Sinica 2014, 35 (1) , 98-112.
    18. A.-S. Dieudonné, D. Lambrechts, D. Smeets, A. Belmans, H. Wildiers, R. Paridaens, C. Hyonil, D. Timmerman, M.-R. Christiaens, I. Vergote, P. Neven. The rs1800716 variant in CYP2D6 is associated with an increased double endometrial thickness in postmenopausal women on tamoxifen. Annals of Oncology 2014, 25 (1) , 90-95.
    19. Juhyun Kim, Christopher C. Coss, Christina M. Barrett, Michael L. Mohler, Casey E. Bohl, Chien‐Ming Li, Yali He, Karen A. Veverka, James T. Dalton. Role and pharmacologic significance of cytochrome P‐450 2D6 in oxidative metabolism of toremifene and tamoxifen. International Journal of Cancer 2013, 132 (6) , 1475-1485.
    20. Mark P. Grillo. Bioactivation by Phase‐ II ‐Enzyme‐Catalyzed Conjugation of Xenobiotics. 2012, 1-56.
    21. E. Gerace, A. Salomone, G. Abbadessa, S. Racca, M. Vincenti. Rapid determination of anti-estrogens by gas chromatography/mass spectrometry in urine: Method validation and application to real samples. Journal of Pharmaceutical Analysis 2012, 2 (1) , 1-11.
    22. Ganesh M. Mugundu, Larry Sallans, Yingying Guo, Elizabeth A. Shaughnessy, Pankaj B. Desai. Assessment of the Impact of CYP3A Polymorphisms on the Formation of α-Hydroxytamoxifen and N -Desmethyltamoxifen in Human Liver Microsomes. Drug Metabolism and Disposition 2012, 40 (2) , 389-396.
    23. Nilesh W. Gaikwad, William J. Bodell. Peroxidase-mediated dealkylation of tamoxifen, detected by electrospray ionization–mass spectrometry, and activation to form DNA adducts. Free Radical Biology and Medicine 2012, 52 (2) , 340-347.
    24. Agnieszka Potega, Emilia Dabrowska, Magdalena Niemira, Agata Kot-Wasik, Sebastien Ronseaux, Colin J. Henderson, C. Roland Wolf, Zofia Mazerska. The Imidazoacridinone Antitumor Drug, C-1311, Is Metabolized by Flavin Monooxygenases but Not by Cytochrome P450s. Drug Metabolism and Disposition 2011, 39 (8) , 1423-1432.
    25. Enrique Ochoa Aranda, Josep Esteve-Romero, Maria Rambla-Alegre, Juan Peris-Vicente, Devasish Bose. Development of a methodology to quantify tamoxifen and endoxifen in breast cancer patients by micellar liquid chromatography and validation according to the ICH guidelines. Talanta 2011, 84 (2) , 314-318.
    26. Noriyuki Koyama, Yasushi Yamazoe. Development of Two-dimensional Template System for the Prediction of CYP2B6-mediated Reaction Sites. Drug Metabolism and Pharmacokinetics 2011, 26 (4) , 309-330.
    27. Helén Andersson, Malin Helmestam, Anna Zebrowska, Matts Olovsson, Eva Brittebo. Tamoxifen-Induced Adduct Formation and Cell Stress in Human Endometrial Glands. Drug Metabolism and Disposition 2010, 38 (1) , 200-207.
    28. Hiltrud Brauch, Thomas E Mürdter, Michel Eichelbaum, Matthias Schwab. Pharmacogenomics of Tamoxifen Therapy. Clinical Chemistry 2009, 55 (10) , 1770-1782.
    29. K. Brown. Is tamoxifen a genotoxic carcinogen in women?. Mutagenesis 2009, 24 (5) , 391-404.
    30. Bernard Testa, Stefanie D. Krämer. The Biochemistry of Drug Metabolism – An Introduction. Chemistry & Biodiversity 2009, 6 (5) , 591-684.
    31. L. Slovacek, V. Ansorgova, Z. Macingova, L. Haman, J. Petera. Tamoxifen-induced QT interval prolongation. Journal of Clinical Pharmacy and Therapeutics 2008, 33 (4) , 453-455.
    32. Caitlin M. Brown, Brad Reisfeld, Arthur N. Mayeno. Cytochromes P450: A Structure-Based Summary of Biotransformations Using Representative Substrates. Drug Metabolism Reviews 2008, 40 (1) , 1-100.

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