Paradoxical effect of an aromatase inhibitor, CGS 20267, on aromatase activity in guinea pig brain.
To determine the effect of in vivo treatment of guinea pigs with a non-steroidal aromatase inhibitor (CGS 20267; letrozole), we treated subjects with subcutaneous Silastic implants containing crystalline letrozole. We studied four treatment groups: intact, intact letrozole-treated, castrate and castrate letrozole-treated. After treatment for 1 week, brain tissues (preoptic area, septum, medial basal hypothalamus, amygdala and parietal cortex) were removed, and microsomal aromatase activity (AA) was determined by an in vitro 3H2O assay using 1beta-3H-androstenedione as substrate. Kinetic experiments were performed to determine the competitive nature of letrozole and an approximate Ki was calculated. Letrozole appears to be a reversible, competitive inhibitor of aromatase activity with an apparent Ki of 1.2 nM. Aromatase activity in intact letrozole-treated animals was elevated compared to untreated controls in all brain areas tested (P< 0.05). Letrozole also stimulated AA in the brains of letrozole-treated castrated guinea pigs compared to untreated castrated animals (P< 0.05). These data indicate that letrozole administered in vivo causes an increase in AA. Possible mechanisms include an autoregulatory mechanism which is interrupted by enzyme inhibition, or an effect of the inhibitor on turnover rates of P450 aromatase.
Department of Physiology and Pharmacology, Oregon Health Sciences University, Portland 97201, U.S.A.
J V
JV
Choate
J A
JA
Resko
D000735:Androstenedione / Q000378:metabolism; D000818:Animals; D047072:Aromatase Inhibitors; D001667:Binding, Competitive; D001921:Brain / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000097:blood; D004970:Estrone / Q000097:blood; D006168:Guinea Pigs; D007700:Kinetics; D000077289:Letrozole; D008297:Male; D008861:Microsomes / Q000201:enzymology; D009570:Nitriles / Q000494:pharmacology*; D009919:Orchiectomy; D013739:Testosterone / Q000097:blood; D014230:Triazoles / Q000494:pharmacology*
D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D009570:Nitriles; D014230:Triazoles; D004970:Estrone; D013739:Testosterone; D000735:Androstenedione; D004958:Estradiol; D000077289:Letrozole