6 alpha-fluorotestosterone: a nonaromatizable androgen inhibitor of aromatase cytochrome P450.
In an early survey of steroids which might serve as estrogen precursors, Gual et al. reported that 6 alpha-fluorotestosterone is not aromatized by human placental microsomes. Subsequently, 6 alpha-fluorotestosterone has been used to distinguish between androgen- and estrogen-mediated physiologic effects. We have reexamined the interaction of 6 alpha-fluorotestosterone with human placental and rat ovarian microsomes and with reconstituted purified aromatase cytochrome P450. Under conditions in which testosterone was readily aromatized, no aromatization of 6 alpha-fluorotestosterone was observed using either fluorescence detection of dansyl-estrogens separated by high-performance liquid chromatography or estrogen radioimmunoassay methods. The lack of aromatization is not due to failure of 6 alpha-fluorotestosterone to bind to P450arom, because 6 alpha-fluorotestosterone acts as a competitive inhibitor of the enzyme, and it exhibits a binding affinity similar to that of testosterone. Moreover, the addition of 6 alpha-fluorotestosterone to human placental microsomes elicits a spectral shift indicative of conversion of the heme from a low to a high spin state as observed for androgen substrates, consistent with its binding to the substrate site. The mechanism by which substitution of a fluorine at the 6 alpha-position interferes with the aromatization reaction remains to be determined, but the inhibitory action on estrogen formation may potentiate the androgenic properties of 6 alpha-fluorotestosterone in vivo due to a lowering of estrogen levels.
Kellis
J T
JT
Department of Physiology and Biophysics, University of California, Irvine 92717.
Vickery
L E
LE
D000818:Animals; D047072:Aromatase Inhibitors; D006801:Humans; D011863:Radioimmunoassay; D051381:Rats; D013739:Testosterone / Q000031:analogs & derivatives* / Q000494:pharmacology
C017321:6-fluorotestosterone; D047072:Aromatase Inhibitors; D013739:Testosterone