17alpha-methyl testosterone is a competitive inhibitor of aromatase activity in Jar choriocarcinoma cells and macrophage-like THP-1 cells in culture.
17alpha-methyl testosterone is a synthetic androgen with affinity for the androgen receptor. 17alpha-methyl testosterone is used widely as a component of hormone replacement therapy. Previous reports have indicated that contrary to testosterone, 17alpha-methyl testosterone is not aromatized. However, 17alpha-methyl testosterone still could affect local estrogen formation by regulating aromatase expression or by inhibiting aromatase action. Both possibilities have important clinical implications. To evaluate the effect of 17alpha-methyl testosterone on the expression and activity of aromatase, we tested the choriocarcinoma Jar cell line, a cell line that express high levels of P450 aromatase, and the macrophage-like THP-1 cells, which express aromatase only after undergoing differentiation. We found that in both cell lines, 17alpha-methyl testosterone inhibits aromatase activity in a dose-related manner. The curve of inhibition parallels that of letrozole and gives complete inhibition at 10(-4) M 17alpha-methyl testosterone, determined by the tritium release assay. 17alpha-methyl testosterone does not have detectable effects on aromatase RNA and protein expression by Jar cells. Undifferentiated THP-1 cells had no aromatase activity and showed no effect of 17alpha-methyl testosterone, but differentiated THP-1 (macrophage-like) cells had a similar inhibition of aromatase activity by 17alpha-methyl testosterone to that seen in Jar cells. The Lineweaver-Burke plot shows 17alpha-methyl testosterone to be a competitive aromatase inhibitor. Our results show for the first time that 17alpha-methyl testosterone acts as an aromatase inhibitor. These findings are relevant for understanding the effects of 17alpha-methyl testosterone as a component of hormone replacement therapy. 17alpha-methyl testosterone may, as a functional androgen and orally active steroidal inhibitor of endogenous estrogen production, also offer special possibilities for the prevention/treatment of hormone-sensitive cancers.
Mor
G
G
Department of Obstetrics and Gynecology, Center for Research in Reproductive Biology and Reproductive Neuroscience Unit, Yale University Medical School, 333 Cedar Street, FMB 335, New Haven, CT 06520 8063, USA.
Eliza
M
M
Song
J
J
Wiita
B
B
Chen
S
S
Naftolin
F
F
D001141:Aromatase / Q000235:genetics; D047072:Aromatase Inhibitors; D001667:Binding, Competitive; D002460:Cell Line; D002822:Choriocarcinoma / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007700:Kinetics; D000077289:Letrozole; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology*; D008777:Methyltestosterone / Q000008:administration & dosage / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics
D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole; D001141:Aromatase; D008777:Methyltestosterone