Aromatase inhibition by R 76 713: a kinetic analysis in rat ovarian homogenates.
Reaction kinetics of the aromatase enzyme and of a new nonsteroidal aromatase inhibitor, R 76 713 (6-[(4-chlorophenyl)(1H-1,2,4-triazol-1-yl)-methyl]-1-methyl-1H- benzotriazole), were studied in ovarian homogenates obtained from pregnant mare's serum gonadotropin (PMSG)-injected female Wistar rats. The Km (Michaelis constant) of the aromatase enzyme with androstenedione as the substrate was 47 +/- 13 nM; for testosterone as the substrate, a value of 159 +/- 10 nM was found. In the presence of increasing concentrations of R 76 713, the Km increased while the Vmax (maximal velocity of enzyme-catalyzed reaction) remained unchanged. Using androstenedione and testosterone as the substrate, Lineweaver-Burk analysis of the data showed a Ki (dissociation constant of the enzyme-inhibitor complex) for R 76 713 of 0.7 +/- 0.3 nM and 1.6 +/- 0.4 nM, respectively. R 76 713 appeared to competitively inhibit the rat ovarian aromatase.
Krekels
M D
MD
Department of Endocrinology and Oncology, Janssen Research Foundation, Beerse, Belgium.
Wouters
W
W
De Coster
R
R
D000735:Androstenedione / Q000378:metabolism; D000818:Animals; D047072:Aromatase Inhibitors; D005260:Female; D007700:Kinetics; D010053:Ovary / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D011919:Rats, Inbred Strains; D013739:Testosterone / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*
D047072:Aromatase Inhibitors; D014230:Triazoles; C060523:vorozole; D013739:Testosterone; D000735:Androstenedione