This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kupfer, D. Articles by Rifkind, A. B. Search for Related Content PubMed PubMed Citation Articles by Kupfer, D. Articles by Rifkind, A. B.

Induction of Tamoxifen-4-hydroxylation by 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), ß-Naphthoflavone (ßNF), and Phenobarbital (PB) in Avian Liver: Identification of P450 TCDD_AA as Catalyst of 4-Hydroxylation Induced by TCDD and ßNF¹

Worcester Foundation for Experimental Biology, Schrewsbury, Massachusetts 01545 [D. K., C. M.], and Department of Pharmacology and Medicine, Cornell University Medical College, New York 10021 [C. A. L., A. B. R.]

Tamoxifen has been found to be metabolized by liver primarily into three metabolites, tamoxifen-N-oxide, formed by the flavin-containing monooxygenase, and N-desmethyl- and 4-hydroxytamoxifen, formed by cytochrome P450. The N-demethylation was demonstrated to be catalyzed by P4503A in rat and human liver; however, the P450s catalyzing the 4-hydroxylation have not been identified. Although 4-hydroxytamoxifen exhibits more potent estrogen agonist/antagonist activity than tamoxifen, the relative contributions of the parent drug and its 4-hydroxy metabolite(s) to the activity of tamoxifen in vivo have not been established. We report here that the rate of tamoxifen 4-hydroxylation is higher in livers of adult chicken and chick embryos than in livers of mammalian species. Tamoxifen 4-hydroxylation was increased by treatment of chick embryos with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), ß-naphthoflavone (ßNF), and to a lesser extent by phenobarbital (PB). The major effect of PB treatment was an increase in tamoxifen N-demethylation. Tamoxifen 4-hydroxylase activity of reconstituted purified chicken P450s was highest for TCDD_AA, a P450 active in arachidonate epoxygenation and estradiol 2-hydroxylation, and one of the two major P450s induced by TCDD and ßNF in chick embryo liver. The second P450, TCDD_AHH, which is active in aryl hydrocarbon hydroxylase and 7-ethoxyresorufin deethylase was inactive in tamoxifen 4-hydroxylation. Anti-TCDD_AA IgG immunoinhibited tamoxifen 4-hydroxylation in microsomes from ßNF-treated embryos by over 80%, but was ineffective against this reaction in the controls. The immunochemical findings together with the reconstitution data identify TCDD_AA as the P450 responsible for TCDD/ßNF-induced tamoxifen 4-hydroxylation in chick liver. In PB-treated livers, a P450 fraction containing CYP2H1/H2, the major PB-induced P450s, had the highest tamoxifen 4-hydroxylase and N-demethylase activities, a finding compatible with one or both of those P450s being responsible for the PB-induced tamoxifen 4-hydroxylation and N-demethylation. The findings reported here raise the possibility that exposure of women undergoing tamoxifen therapy to agents that induce human CYP1A2 or CYP2B1/2 analogues may produce increased levels of 4-hydroxytamoxifen and that this may affect the therapeutic potency of tamoxifen.

¹ This work was supported by USPHS Grants ES00834 (D. K.) and ESO3606 (A. B. R.) from the National Institute of Environmental Health Sciences. A preliminary report of this investigation was presented at the ASBMB-ACS Joint Meeting in San Diego, CA, May 30–June 3, 1993 (35).

² To whom requests for reprints should be addressed.

Received 3/ 4/94. Accepted 4/20/94.

This article has been cited by other articles:

				S. S. Dehal and D. Kupfer 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., June 1, 1999; 27(6): 681 - 688. [Abstract] [Full Text]

				S. S. Dehal, A. M. H. Brodie, and D. Kupfer 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., March 1, 1999; 27(3): 389 - 394. [Abstract] [Full Text]

				J. A. Thomas Drugs and Chemicals that Affect the Endocrine System International Journal of Toxicology, February 1, 1998; 17(2): 129 - 138. [Abstract] [PDF]

				P. R. Sinclair, N. Gorman, H. S. Walton, J. F. Sinclair, C. A. Lee, and A. B. Rifkind Identification of CYP1A5 as the CYP1A Enzyme Mainly Responsible for Uroporphyrinogen Oxidation Induced by Ah Receptor Ligands in Chicken Liver and Kidney Drug Metab. Dispos., July 1, 1997; 25(7): 779 - 783. [Abstract] [Full Text]