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The aromatase inactivator 4-hydroxyandrostenedione (4-OH-A) inhibits tamoxifen metabolism by rat hepatic cytochrome P-450 3A: potential for drug-drug interaction of tamoxifen and 4-OH-A in combined anti-breast cancer therapy.
Drug Metab Dispos. 1999 Mar; 27(3):389-94.DM

Abstract

Tamoxifen (tam), an anti-breast cancer agent, is metabolized into tam-N-oxide by the hepatic flavin-containing monooxygenase and into N-desmethyl- and 4-hydroxy-tam by cytochrome P-450s (CYPs). Additionally, tam is metabolically activated by hepatic CYP3A, forming a reactive intermediate that binds covalently to proteins. Tam and 4-hydroxyandrostenedione (4-OH-A) are currently used to treat breast cancer, and it has been contemplated that 4-OH-A be given concurrently with tam to contravene potential tumor resistance to tam. Because alterations in tam metabolism may influence its therapeutic efficacy, the effect of 4-OH-A on tam metabolism was examined. Incubation of tam with liver microsomes from phenobarbital-treated rats, in the presence of 4-OH-A (10-100 microM), resulted in marked inhibition of tam-N-demethylation and tam covalent binding and in decreased tam-N-oxide accumulation; however, there was no inhibition of the formation of 4-hydroxy-tam and of 3,4-dihydroxytamoxifen. These findings indicate that 4-OH-A inhibits CYP3A, but not P-450(s) that catalyze tam 4-hydroxylation. The diminished tam-N-oxide accumulation could be due to decreased N-oxide formation and/or due to increased N-oxide reduction. Incubation of tam-N-oxide with liver microsomes containing heat-inactivated flavin-containing monooxygenase demonstrated that 4-OH-A increases the accumulation of tam, possibly by diminishing its P-450-mediated metabolism. Kinetic studies indicate that 4-OH-A is a competitive inhibitor of CYP3A, but not a time-dependent inactivator. Consequently, the concurrent treatment of tam and 4-OH-A may result in increased tam half-life and thus could potentiate the therapeutic efficacy of tam and diminish the potential side effects of tam by inhibiting its covalent binding to proteins and possibly to DNA.

Authors+Show Affiliations

Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical Center, Worcester, Massachusetts, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

10064571

Citation

Dehal, S S., et al. "The Aromatase Inactivator 4-hydroxyandrostenedione (4-OH-A) Inhibits Tamoxifen Metabolism By Rat Hepatic Cytochrome P-450 3A: Potential for Drug-drug Interaction of Tamoxifen and 4-OH-A in Combined Anti-breast Cancer Therapy." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 27, no. 3, 1999, pp. 389-94.
Dehal SS, Brodie AM, Kupfer D. The aromatase inactivator 4-hydroxyandrostenedione (4-OH-A) inhibits tamoxifen metabolism by rat hepatic cytochrome P-450 3A: potential for drug-drug interaction of tamoxifen and 4-OH-A in combined anti-breast cancer therapy. Drug Metab Dispos. 1999;27(3):389-94.
Dehal, S. S., Brodie, A. M., & Kupfer, D. (1999). The aromatase inactivator 4-hydroxyandrostenedione (4-OH-A) inhibits tamoxifen metabolism by rat hepatic cytochrome P-450 3A: potential for drug-drug interaction of tamoxifen and 4-OH-A in combined anti-breast cancer therapy. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 27(3), 389-94.
Dehal SS, Brodie AM, Kupfer D. The Aromatase Inactivator 4-hydroxyandrostenedione (4-OH-A) Inhibits Tamoxifen Metabolism By Rat Hepatic Cytochrome P-450 3A: Potential for Drug-drug Interaction of Tamoxifen and 4-OH-A in Combined Anti-breast Cancer Therapy. Drug Metab Dispos. 1999;27(3):389-94. PubMed PMID: 10064571.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The aromatase inactivator 4-hydroxyandrostenedione (4-OH-A) inhibits tamoxifen metabolism by rat hepatic cytochrome P-450 3A: potential for drug-drug interaction of tamoxifen and 4-OH-A in combined anti-breast cancer therapy. AU - Dehal,S S, AU - Brodie,A M, AU - Kupfer,D, PY - 1999/3/4/pubmed PY - 1999/3/4/medline PY - 1999/3/4/entrez SP - 389 EP - 94 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 27 IS - 3 N2 - Tamoxifen (tam), an anti-breast cancer agent, is metabolized into tam-N-oxide by the hepatic flavin-containing monooxygenase and into N-desmethyl- and 4-hydroxy-tam by cytochrome P-450s (CYPs). Additionally, tam is metabolically activated by hepatic CYP3A, forming a reactive intermediate that binds covalently to proteins. Tam and 4-hydroxyandrostenedione (4-OH-A) are currently used to treat breast cancer, and it has been contemplated that 4-OH-A be given concurrently with tam to contravene potential tumor resistance to tam. Because alterations in tam metabolism may influence its therapeutic efficacy, the effect of 4-OH-A on tam metabolism was examined. Incubation of tam with liver microsomes from phenobarbital-treated rats, in the presence of 4-OH-A (10-100 microM), resulted in marked inhibition of tam-N-demethylation and tam covalent binding and in decreased tam-N-oxide accumulation; however, there was no inhibition of the formation of 4-hydroxy-tam and of 3,4-dihydroxytamoxifen. These findings indicate that 4-OH-A inhibits CYP3A, but not P-450(s) that catalyze tam 4-hydroxylation. The diminished tam-N-oxide accumulation could be due to decreased N-oxide formation and/or due to increased N-oxide reduction. Incubation of tam-N-oxide with liver microsomes containing heat-inactivated flavin-containing monooxygenase demonstrated that 4-OH-A increases the accumulation of tam, possibly by diminishing its P-450-mediated metabolism. Kinetic studies indicate that 4-OH-A is a competitive inhibitor of CYP3A, but not a time-dependent inactivator. Consequently, the concurrent treatment of tam and 4-OH-A may result in increased tam half-life and thus could potentiate the therapeutic efficacy of tam and diminish the potential side effects of tam by inhibiting its covalent binding to proteins and possibly to DNA. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/10064571/The_aromatase_inactivator_4_hydroxyandrostenedione__4_OH_A__inhibits_tamoxifen_metabolism_by_rat_hepatic_cytochrome_P_450_3A:_potential_for_drug_drug_interaction_of_tamoxifen_and_4_OH_A_in_combined_anti_breast_cancer_therapy_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10064571 DB - PRIME DP - Unbound Medicine ER -