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Oxidation of tamoxifen by human flavin-containing monooxygenase (FMO) 1 and FMO3 to tamoxifen-N-oxide and its novel reduction back to tamoxifen by human cytochromes P450 and hemoglobin.
Drug Metab Dispos. 2005 Oct; 33(10):1446-52.DM

Abstract

Tamoxifen (TAM), used as the endocrine therapy of choice for breast cancer, undergoes metabolism primarily forming N-desmethyltamoxifen, 4-hydroxytamoxifen, alpha-hydroxytamoxifen, and tamoxifen-N-oxide (TNO). Our earlier studies demonstrated that flavin-containing monooxygenases (FMOs) catalyze the formation of TNO. The current study demonstrates that human FMO1 and FMO3 catalyze TAM N-oxidation to TNO and that cytochromes P450 (P450s), but not FMOs, reduce TNO to TAM. CYP1A1, CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 all reduced TNO, with CYP2A6, CYP1A1, and CYP3A4 producing the greatest reduction. A portion of TAM formed by CYP3A4-mediated reduction of TNO was further metabolized, but not TAM formed by the other P450s. TNO reduction by P450s is extremely rapid with considerable TAM formation detected at the earliest time point that products could be measured. TAM formation exhibited a lack of linearity with incubation time but increased linearly as a function of TNO and P450 concentration. TNO was converted into TAM by reduced hemoglobin (Hb) and NADPH-P450 oxidoreductase, suggesting involvement of the same heme-Fe(2+) complex in both Hb and P450s. The findings raise the question of whether the reductive activity may be nonenzymatic. Results of this in vitro study demonstrate the potential of TAM and TNO to be interconverted metabolically. FMO seems to be the major enzymatic oxidant, whereas several P450 enzymes and even reduced hemoglobin are capable of reducing TNO back to TAM. The possibility that these processes may comprise a metabolic cycle in vivo is discussed in this article.

Authors+Show Affiliations

Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, USA. priyankaparte@rediffmail.comNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15987777

Citation

Parte, Priyanka, and David Kupfer. "Oxidation of Tamoxifen By Human Flavin-containing Monooxygenase (FMO) 1 and FMO3 to tamoxifen-N-oxide and Its Novel Reduction Back to Tamoxifen By Human Cytochromes P450 and Hemoglobin." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 33, no. 10, 2005, pp. 1446-52.
Parte P, Kupfer D. Oxidation of tamoxifen by human flavin-containing monooxygenase (FMO) 1 and FMO3 to tamoxifen-N-oxide and its novel reduction back to tamoxifen by human cytochromes P450 and hemoglobin. Drug Metab Dispos. 2005;33(10):1446-52.
Parte, P., & Kupfer, D. (2005). Oxidation of tamoxifen by human flavin-containing monooxygenase (FMO) 1 and FMO3 to tamoxifen-N-oxide and its novel reduction back to tamoxifen by human cytochromes P450 and hemoglobin. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 33(10), 1446-52.
Parte P, Kupfer D. Oxidation of Tamoxifen By Human Flavin-containing Monooxygenase (FMO) 1 and FMO3 to tamoxifen-N-oxide and Its Novel Reduction Back to Tamoxifen By Human Cytochromes P450 and Hemoglobin. Drug Metab Dispos. 2005;33(10):1446-52. PubMed PMID: 15987777.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Oxidation of tamoxifen by human flavin-containing monooxygenase (FMO) 1 and FMO3 to tamoxifen-N-oxide and its novel reduction back to tamoxifen by human cytochromes P450 and hemoglobin. AU - Parte,Priyanka, AU - Kupfer,David, Y1 - 2005/06/29/ PY - 2005/7/1/pubmed PY - 2006/4/6/medline PY - 2005/7/1/entrez SP - 1446 EP - 52 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 33 IS - 10 N2 - Tamoxifen (TAM), used as the endocrine therapy of choice for breast cancer, undergoes metabolism primarily forming N-desmethyltamoxifen, 4-hydroxytamoxifen, alpha-hydroxytamoxifen, and tamoxifen-N-oxide (TNO). Our earlier studies demonstrated that flavin-containing monooxygenases (FMOs) catalyze the formation of TNO. The current study demonstrates that human FMO1 and FMO3 catalyze TAM N-oxidation to TNO and that cytochromes P450 (P450s), but not FMOs, reduce TNO to TAM. CYP1A1, CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 all reduced TNO, with CYP2A6, CYP1A1, and CYP3A4 producing the greatest reduction. A portion of TAM formed by CYP3A4-mediated reduction of TNO was further metabolized, but not TAM formed by the other P450s. TNO reduction by P450s is extremely rapid with considerable TAM formation detected at the earliest time point that products could be measured. TAM formation exhibited a lack of linearity with incubation time but increased linearly as a function of TNO and P450 concentration. TNO was converted into TAM by reduced hemoglobin (Hb) and NADPH-P450 oxidoreductase, suggesting involvement of the same heme-Fe(2+) complex in both Hb and P450s. The findings raise the question of whether the reductive activity may be nonenzymatic. Results of this in vitro study demonstrate the potential of TAM and TNO to be interconverted metabolically. FMO seems to be the major enzymatic oxidant, whereas several P450 enzymes and even reduced hemoglobin are capable of reducing TNO back to TAM. The possibility that these processes may comprise a metabolic cycle in vivo is discussed in this article. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/15987777/Oxidation_of_tamoxifen_by_human_flavin_containing_monooxygenase__FMO__1_and_FMO3_to_tamoxifen_N_oxide_and_its_novel_reduction_back_to_tamoxifen_by_human_cytochromes_P450_and_hemoglobin_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15987777 DB - PRIME DP - Unbound Medicine ER -