INHIBITION OF AROMATASE-ACTIVITY IN HUMAN PLACENTAL MICROSOMES BY 13-RETRO-ANTIPROGESTINS

Mifepristone (RU 486), used clinically for the termination of early pr egnancy, and its acetyl and 13-retro (13 alpha) analogs show potent an tiproliferative effects against estrogen-dependent human breast tumors and endometriosis. However, there has been no report on direct inhibi tion of aromatase by antiprogesterones. Aromatase inhibitors have been shown to be effective against estrogen-dependent breast cancer. We ev aluated the inhibition of aromatase by various antiprogestins (ZK 112. 993, ZK 98.734, ZK 114.043, ZK 98.299, and ZK 114.863). Human placenta l microsomes were incubated with [1 beta-H-3,4-C-14]androstenedione (3 -114 nM) in the presence of NADPH, with or without putative inhibitors (10-200 mu M) Aromatase activity was assessed by tritium release to w ater from the 1 beta-position of the substrate. ZK 112.993 and ZK 98.7 34 did not show any inhibitory effect. The statistical analysis of the data using standard errors was obtained from replicate experiments. Z K 114.043 showed slight inhibition with a K-i of 54.8 +/- 6.4 mu M (m +/- SE, n = 6) against androstenedione aromatization. The two 13-retro -steroids, ZK 98.299 and ZK 114.863, showed aromatase inhibition with K-i values of 19.0 +/- 1.5 mu M (n = 7) and 12.7 +/- 0.94 mu M (n = 7) , respectively, which is weak with respect to some known potent inhibi tors, but significant when compared with the other antiprogestins whic h were tested. The results suggest that the unnatural 13-retro-antipro gestin conformation may have a better fit to the aromatase active site than the natural 13 beta-antiprogestin conformation.