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Inhibition of estrogen production provides effective therapy for patients with hormone-dependent breast cancer. The source of estrogens in premenopausal women is predominantly the ovary, but after the menopause, estradiol is synthesized in peripheral tissues through the aromatization of androgens to estrogens. Uptake from plasma is the primary mechanism for maintenance of estradiol concentrations in breast cancer tissue in premenopausal women, whereas several steps may be operant in postmenopausal women. These include enzymatic synthesis of estradiol via sulfatase, aromatase, and 17 beta-hydroxysteroid dehydrogenase in the tumor itself. Aromatization of androgens secreted by the adrenal to estrogens in peripheral tissues and transport to the tumor via circulation in the plasma provides another means of maintaining breast tumor estradiol levels in postmenopausal women. These various sources contribute to the high tissue estrogen levels measured in breast tumor tissue. To effectively suppress tissue concentrations of estrogens and circulating estradiol in postmenopausal patients, various aromatase inhibitors have been developed recently. These include steroidal inhibitors such as 4-hydroxy-androstenedione as well as non-steroidal compounds with imidazole and triazole structures. The most potent of these, CGS 20267, is reported to suppress levels of active estrogens (i.e., estrone, estrone sulfatase, and estradiol) by more than 95%. This compound can suppress both serum and 24-hr urine estrogens to a greater extent than produced by the second generation inhibitor, CGS 16949A. CGS 20267 is highly specific since it does not affect cortisol and aldosterone serum levels during ACTH stimulation tests nor sodium and potassium balance in 24-hr urine samples.(ABSTRACT TRUNCATED AT 250 WORDS)
Inhibition of estrogen production provides effective therapy for patients with hormone-dependent breast cancer. The source of estrogens in premenopausal women is predominantly the ovary, but after the menopause, estradiol is synthesized in peripheral tissues through the aromatization of androgens to estrogens. Uptake from plasma is the primary mechanism for maintenance of estradiol concentrations in breast cancer tissue in premenopausal women, whereas several steps may be operant in postmenopausal women. These include enzymatic synthesis of estradiol via sulfatase, aromatase, and 17 beta-hydroxysteroid dehydrogenase in the tumor itself. Aromatization of androgens secreted by the adrenal to estrogens in peripheral tissues and transport to the tumor via circulation in the plasma provides another means of maintaining breast tumor estradiol levels in postmenopausal women. These various sources contribute to the high tissue estrogen levels measured in breast tumor tissue. To effectively suppress tissue concentrations of estrogens and circulating estradiol in postmenopausal patients, various aromatase inhibitors have been developed recently. These include steroidal inhibitors such as 4-hydroxy-androstenedione as well as non-steroidal compounds with imidazole and triazole structures. The most potent of these, CGS 20267, is reported to suppress levels of active estrogens (i.e., estrone, estrone sulfatase, and estradiol) by more than 95%. This compound can suppress both serum and 24-hr urine estrogens to a greater extent than produced by the second generation inhibitor, CGS 16949A. CGS 20267 is highly specific since it does not affect cortisol and aldosterone serum levels during ACTH stimulation tests nor sodium and potassium balance in 24-hr urine samples.(ABSTRACT TRUNCATED AT 250 WORDS)
Several purified isoforms of microsomal cytochrome P450 were previously shown in this laboratory to catalyze the oxidative deformylation of a variety of alpha- or beta-branched aldehydes with the production of olefins and formic acid. In the present study, 3-oxodecalin-4-ene-10-carboxaldehyde (ODEC, numbered according to the convention for steroids) was synthesized as a bicyclic analog of the aldehyde that is known to be the terminal intermediate in the enzymatic conversion of androgens to estrogens. ODEC undergoes aromatization in a reconstituted enzyme system containing liver microsomal cytochrome P450 2B4 and NADPH-cytochrome P450 reductase, along with NADPH and phosphatidylcholine, under aerobic conditions. The products, 3-hydroxy-6,7,8,9-tetrahydronaphthalene (HTN) and formic acid, were identified by mass spectrometry. The corresponding 10-carbinol does not undergo oxidative aromatization with P450 2B4, and with ODEC as substrate, other microsomal P450 cytochromes are either weakly active (isoforms 2C3 and 3A6) or inactive (isoforms 2E1, 1A2, and 2G1). Cytochrome b5 stimulates the P450 2B4-catalyzed reaction with ODEC about 2.6-fold but has no effect with the other P450s. In two respects the conversion of the bicyclic model compound to HTN with P450 2B4 was shown to be similar to that of the steroid aromatase reaction. Deuterium in the formyl group of ODEC was retained in the formic acid that was produced and isolated as the 4-nitrobenzyl derivative, and with preparations of ODEC containing deuterium in the 1 alpha position or the 1 alpha and 2 alpha positions, it was shown that the desaturation reaction is specific for removal of the 1 beta-hydrogen, thus involving a stereospecific cis elimination of formate. Cytochrome b5 has no effect on the stereospecificity of the reaction.
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