6α-Fluorotestosterone: a nonaromatizable androgen inhibitor of aromatase cytochrome P450

Article abstract of DOI:10.1016/0039-128X(90)90023-5

In an early survey of steroids which might serve as estrogen precursors, Gual et al. reported that 6α-fluorotestosterone is not aromatized by human placental microsomes.Subsequently, 6α-fluorotestosterone has been used to distinguish between androgen- and estrogen-mediated physiologic effects.We have reexamined the interaction of 6α-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 6α-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 6α-fluorotestosterone to bind P450_arom, because 6α-fluorotestosterone acts as a competitive inhibitor of the enzyme, and it exhibits a binding affinity similar to that of testosterone.Moreover, the addition of 6α-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, cosistent with its binding to the substrate site.The mechanism by which substitution of a fluorine at the 6α-position interferes with the aromatization reaction remains to be determined, but the inhibitory action on estrogen formation may potentiate the androgenic properties of 6α-fluorotestosterone in vivo due to a lowering of estrogen levels.