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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.

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