title: Inhibition of estrone sulfatase enzyme in human placenta and human breast carcinoma.
abstract: Estrone sulfatase is an important mechanism of local synthesis of biologically active estrogens in human breast cancer. The human placental microsome and breast carcinoma mitochondrial/microsomal estrone sulfatase activity were characterized and inhibition studies performed. The Km of the placental tissue enzyme was 6.83 microM, Vmax 0.015 nmol/min/mg, and for the breast carcinoma tissue Km was 8.91 microM and Vmax 0.022 nmol/min/mg. Danazol produced a significant inhibition of estrone sulfatase (20% with 50 microM danazol). No significant inhibition was seen in the presence of aminoglutethimide, rogletimide, tamoxifen, 4-hydroxyandrostenedione, stilboestrol, or any metabolites of danazol or tamoxifen. Studies with synthetic and naturally occurring steroids demonstrated that the presence of a sulfate group at the 3 position to be the most important factor in determining inhibition, and the most potent inhibitor was 5 alpha-androstene-3 beta,17 beta-diol-3-sulfate (Ki of 2.0 microM). The naturally occurring 3-sulfated steroids all demonstrated competitive inhibition. These studies could form the basis for the design of a potent estrone sulfatase inhibitor which would have potential therapeutic activity in the management of breast cancer.
authors.affiliation: Department of Medical Oncology, Charing Cross Hospital, London, England.
authors.forename: T R
authors.initials: TR
authors.lastname: Evans
authors.forename: M G
authors.initials: MG
authors.lastname: Rowlands
authors.forename: M
authors.initials: M
authors.lastname: Jarman
authors.forename: R C
authors.initials: RC
authors.lastname: Coombes
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000201:enzymology*; D002467:Cell Nucleus / Q000201:enzymology; D003613:Danazol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007700:Kinetics; D008861:Microsomes / Q000201:enzymology; D008928:Mitochondria / Q000201:enzymology; D010920:Placenta / Q000201:enzymology*; D011247:Pregnancy; D013379:Substrate Specificity; D013429:Sulfatases / Q000037:antagonists & inhibitors*
chemical_list: D000728:Androgens; D004965:Estrogen Antagonists; D004967:Estrogens; D013429:Sulfatases; C020121:estrone sulfatase; D003613:Danazol