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Metabolism of the antimammary cancer antiestrogenic agent tamoxifen. II. Flavin-containing monooxygenase-mediated N-oxidation.
Drug Metab Dispos. 1993 Jul-Aug; 21(4):657-61.DM

Abstract

Earlier studies demonstrated that the major metabolites of tamoxifen generated by mammalian liver microsomes are the corresponding N-oxide, N-desmethyl, and 4-hydroxy derivatives. This study examines the enzymatic activity catalyzing the formation of tamoxifen N-oxide by mammalian liver microsomes. Incubations of tamoxifen with liver microsomes from the various species, supplemented with NADPH, yielded the N-oxide, N-desmethyl, and 4-hydroxy derivatives. Inhibition of N-oxide accumulation by mild heat and low concentrations of methimazole in rat liver microsomes indicated that this reaction is catalyzed by the flavin-containing monooxygenase (FMO). Antibodies to NADPH-P-450 reductase inhibited N-demethylation and 4-hydroxylation, but not N-oxidation, supporting the aforementioned conclusion. Purified mouse liver microsomal FMO converted tamoxifen solely into the N-oxide, providing direct evidence for FMO involvement. Human liver microsomes formed the same tamoxifen metabolites, albeit at a much lower rate. Inhibitors of FMO diminished the accumulation of N-oxide by human liver microsomes, indicating involvement of FMO. Tamoxifen-N-oxide was found to be readily reduced to tamoxifen by rat or human liver microsomes, in the presence of NADPH; the extent of reduction was dramatically increased when incubations were supplemented with methimazole. The facile reduction of tamoxifen N-oxide back to tamoxifen suggests that the N-oxide may serve as a storage form for tamoxifen in vivo.

Authors+Show Affiliations

Worcester Foundation for Experimental Biology, Shrewsbury, MA 01545.No affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

8104125

Citation

Mani, C, et al. "Metabolism of the Antimammary Cancer Antiestrogenic Agent Tamoxifen. II. Flavin-containing Monooxygenase-mediated N-oxidation." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 21, no. 4, 1993, pp. 657-61.
Mani C, Hodgson E, Kupfer D. Metabolism of the antimammary cancer antiestrogenic agent tamoxifen. II. Flavin-containing monooxygenase-mediated N-oxidation. Drug Metab Dispos. 1993;21(4):657-61.
Mani, C., Hodgson, E., & Kupfer, D. (1993). Metabolism of the antimammary cancer antiestrogenic agent tamoxifen. II. Flavin-containing monooxygenase-mediated N-oxidation. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 21(4), 657-61.
Mani C, Hodgson E, Kupfer D. Metabolism of the Antimammary Cancer Antiestrogenic Agent Tamoxifen. II. Flavin-containing Monooxygenase-mediated N-oxidation. Drug Metab Dispos. 1993 Jul-Aug;21(4):657-61. PubMed PMID: 8104125.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Metabolism of the antimammary cancer antiestrogenic agent tamoxifen. II. Flavin-containing monooxygenase-mediated N-oxidation. AU - Mani,C, AU - Hodgson,E, AU - Kupfer,D, PY - 1993/7/1/pubmed PY - 1993/7/1/medline PY - 1993/7/1/entrez SP - 657 EP - 61 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 21 IS - 4 N2 - Earlier studies demonstrated that the major metabolites of tamoxifen generated by mammalian liver microsomes are the corresponding N-oxide, N-desmethyl, and 4-hydroxy derivatives. This study examines the enzymatic activity catalyzing the formation of tamoxifen N-oxide by mammalian liver microsomes. Incubations of tamoxifen with liver microsomes from the various species, supplemented with NADPH, yielded the N-oxide, N-desmethyl, and 4-hydroxy derivatives. Inhibition of N-oxide accumulation by mild heat and low concentrations of methimazole in rat liver microsomes indicated that this reaction is catalyzed by the flavin-containing monooxygenase (FMO). Antibodies to NADPH-P-450 reductase inhibited N-demethylation and 4-hydroxylation, but not N-oxidation, supporting the aforementioned conclusion. Purified mouse liver microsomal FMO converted tamoxifen solely into the N-oxide, providing direct evidence for FMO involvement. Human liver microsomes formed the same tamoxifen metabolites, albeit at a much lower rate. Inhibitors of FMO diminished the accumulation of N-oxide by human liver microsomes, indicating involvement of FMO. Tamoxifen-N-oxide was found to be readily reduced to tamoxifen by rat or human liver microsomes, in the presence of NADPH; the extent of reduction was dramatically increased when incubations were supplemented with methimazole. The facile reduction of tamoxifen N-oxide back to tamoxifen suggests that the N-oxide may serve as a storage form for tamoxifen in vivo. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/8104125/Metabolism_of_the_antimammary_cancer_antiestrogenic_agent_tamoxifen__II__Flavin_containing_monooxygenase_mediated_N_oxidation_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=8104125 DB - PRIME DP - Unbound Medicine ER -