TY - JOUR
T1 - The effects of in vivo administration of 10-propargylestr-4-ene-3,17-dione on rat ovarian aromatase and estrogen levels
AU - Brandt, Mark E.
AU - Covey, Douglas F.
AU - Zimniski, Stephen J.
N1 - Funding Information:
The authors wish to thank Karin Fendl for her assistance with the experiments and during the preparation of the manuscript. This research was supported by NIH grants CA43226, CA23582, and DK33913.
PY - 1990
Y1 - 1990
N2 - We have previously demonstrated that 10-propargylestr-4-ene-3,17-dione (PED) functioned as an irreversible inhibitor of rat ovarian aromatase in vitro. These studies were undertaken to examine the in vivo effects of PED on rat ovarian aromatase activity and estrogen production. In the current experiments, a single injection of PED (0.5 or 2.5mg/kg) was found to maximally inhibit aromatase at 3h regardless of dose. Significant inhibition of enzyme activity by PED was observed beyond 18 h, although some recovery was noted at the lower dose (0.5mg/kg). Concomitantly, ovarian estrogen levels were also maximally reduced at 3 h, however ovarian estrogen levels returned toward control values prior to the recovery in enzyme activity. Even though significant inhibition of enzyme activity was observed at 12 h following a single injection of PED, the effect of double injections of the inhibitor at 12 h intervals was surprisingly not cumulative. Similarly, continued multiple injections of PED revealed significant inhibition of enzyme activity and estrogen production several hours after the injection, but variations in effectiveness were observed by 12 h which changed in accordance with a circannual cycle in aromatase. Apparently other factors are involved with maintaining aromatase levels and compensating for reduced enzyme activity. These mechanisms are evidenced by a continuation of the rat reproductive cycle with prolonged PED administration and a reduced influence of PED in regard to enzyme inhibition at certain times of the year. Despite these variations in the duration of action of PED, no comparable changes were observed in effectiveness as an anti-tumor agent. These results suggest that complex mechanisms exist which regulate the activity of aromatase in order to maintain estrogen production. Further research using compounds such as PED may assist in elucidating the factors that modulate ovarian estrogen production.
AB - We have previously demonstrated that 10-propargylestr-4-ene-3,17-dione (PED) functioned as an irreversible inhibitor of rat ovarian aromatase in vitro. These studies were undertaken to examine the in vivo effects of PED on rat ovarian aromatase activity and estrogen production. In the current experiments, a single injection of PED (0.5 or 2.5mg/kg) was found to maximally inhibit aromatase at 3h regardless of dose. Significant inhibition of enzyme activity by PED was observed beyond 18 h, although some recovery was noted at the lower dose (0.5mg/kg). Concomitantly, ovarian estrogen levels were also maximally reduced at 3 h, however ovarian estrogen levels returned toward control values prior to the recovery in enzyme activity. Even though significant inhibition of enzyme activity was observed at 12 h following a single injection of PED, the effect of double injections of the inhibitor at 12 h intervals was surprisingly not cumulative. Similarly, continued multiple injections of PED revealed significant inhibition of enzyme activity and estrogen production several hours after the injection, but variations in effectiveness were observed by 12 h which changed in accordance with a circannual cycle in aromatase. Apparently other factors are involved with maintaining aromatase levels and compensating for reduced enzyme activity. These mechanisms are evidenced by a continuation of the rat reproductive cycle with prolonged PED administration and a reduced influence of PED in regard to enzyme inhibition at certain times of the year. Despite these variations in the duration of action of PED, no comparable changes were observed in effectiveness as an anti-tumor agent. These results suggest that complex mechanisms exist which regulate the activity of aromatase in order to maintain estrogen production. Further research using compounds such as PED may assist in elucidating the factors that modulate ovarian estrogen production.
KW - Aromatase
KW - Aromatase inhibitors
KW - Estrous cycle
KW - Ovarian steroid levels
UR - http://www.scopus.com/inward/record.url?scp=0025608592&partnerID=8YFLogxK
U2 - 10.3109/14756369009040736
DO - 10.3109/14756369009040736
M3 - Article
C2 - 2098521
AN - SCOPUS:0025608592
SN - 1475-6366
VL - 4
SP - 143
EP - 152
JO - Journal of Enzyme Inhibition and Medicinal Chemistry
JF - Journal of Enzyme Inhibition and Medicinal Chemistry
IS - 2
ER -