DEMETHYLIERUNG VON METHOXYÖSTROGENEN IN VITRO UND IN VIVO

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Abstract
The microsomal fraction of rat liver contains an enzyme system which, in the presence of NADPH2 and oxygen, demethylates 2-methoxyoestradiol-17β to 2-hydroxyoestradiol-17β. Under similar experimental conditions, 3-methoxyoestradiol-17β is demethylated to oestradiol-17β. The demethylation of 3-methoxyoestradiol-17β shows an optimum at pH 7.4 and is inhibited by β-diethylaminoethyl diphenylpropylacetate; the type of inhibition seems to be noncompetitive. The Michaelis-Menten constant for 3-methoxyoestradiol-17β was found to be 2.0 × 10−4 m. It appears that demethylation of 2- and 3-methoxyoestrogens is catalysed by a non-specific ether-cleaving enzyme system. After intravenous injection of 20 mg of 3-methoxyoestradiol-17β into 3 patients, the excretion of oestradiol-17β, oestrone and oestriol in the urine showed a marked increase. The average yield of the 3 urinary oestrogens derived from 3-methoxyoestradiol-17β was 2.7% of the dose administered. By using corrections for metabolic and method losses, a demethylation rate of 17.5% for 3-methoxyoestradiol-17β was calculated. The concentrations of oestradiol-17β, oestrone and oestriol in bile also increased after intravenous administration of 3-methoxyoestradiol-17β. The maximum concentrations of oestrone and oestradiol-17β were found immediately after injection, whereas the maximum in the oestriol fraction occurred 4 h later. Oestrone was predominantly excreted in the sulphate fraction, but most of the oestriol was found in the glucuronoside fraction. These results suggest that demethylation of methoxyoestrogens takes place in liver. Some of the biochemical and physiological aspects of demethylation are discussed.

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