Metabolism of the Antiandrogenic Drug (Flutamide) by Human CYP1A2

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Vol. 25, Issue 11, 1298-1303, 1997

Metabolism of the Antiandrogenic Drug (Flutamide) by Human CYP1A2

Manjunath S. Shet, Michael McPhaul, Charles W. Fisher, Nancy R. Stallings, and Ronald W. Estabrook

Department of Biochemistry and the Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas

The antiandrogenic drug, flutamide, is widely used in the treatment of carcinoma of the prostate. The present study examinesthe metabolism of flutamide by human liver microsomes and purifiedrecombinant human cytochrome P450s (CYP), expressed as fusionproteins. These studies show the principal role of CYP1A2 in themetabolism of flutamide to 2-hydroxyflutamide. A minor metaboliteis formed during the metabolism of flutamide by CYP3A4 in thepresence of an excess of added purified NADPH-P450 reductase.

The metabolism of flutamide is inhibited by low concentrations of $alpha$ -naphthoflavone and ketoconazole. Other substrates of CYP1A2,such as phenacetin, imipramine, caffeine, and estradiol, are alsoinhibitors of flutamide metabolism by CYP1A2. Of interest is theinhibition of flutamide metabolism by its metabolite, 2-hydroxyflutamide,and the inhibition of the 2- and 4- hydroxylation of estradiolby flutamide.

CV1 cells do not metabolize flutamide to 2-hydroxyflutamide. In assays performed using this cell line transfected with thecDNA for the androgen receptor, flutamide is a pure antagonist,and 2-hydroxyflutamide, while a more potent androgen receptor(AR) antagonist, activates the AR at higher concentrations. Stableexpression of CYPIA2 in these CV1 cells causes flutamide to exhibitagonistic properties at higher concentrations, a behavior notexhibited by cells stably transfected only with the expressionvector encoding the AR. These findings raise the possibility thatincreased conversion of flutamide to 2-hydroxyflutamide or accumulationof 2-hydroxyflutamide in cells may contribute to the anomalousresponses to flutamide that are observed in some advanced prostatecancers.

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