NOVEL STEROID 5-ALPHA-REDUCTASE INHIBITOR FK143 - ITS DUAL INHIBITIONAGAINST THE 2 ISOZYMES AND ITS EFFECT ON TRANSCRIPTION OF THE ISOZYMEGENES

Recent cloning of the cDNAs for the two isozymes of steroid 5 alpha-re ductase (EC 1.3.99.5) allowed individual expression of the isozymes an d permitted us to investigate the action of steroid 5 alpha-reductase inhibitors against the individual isozymes without any ambiguity that may be caused by coexistence of the isozymes in tissue preparations. W e examined the kinetic characteristics of FK143 lphenyl)methylamino]be nzoyl]-1H-indol-1-yl]butyric acid), a novel nonsteroidal steroid 5 alp ha-reductase inhibitor against cloned human and rat steroid 5 alpha-re ductase isozymes. FK143 was shown to inhibit both isozymes equally. Th e mode of the inhibition of FK143 against both isozymes was noncompeti tive. The inhibition constants K-ie and K-ies of FK143 for human types 1 and 2 were 27.0 and 19.6 nM and 19.9 and 14.5 nM, respectively. Spe cies selectivity between human and rat of the inhibitory activity of F K143 against both isozymes was not found. We also examined the effect of FK143 on the in vivo expression of the genes encoding for the rat s teroid 5 alpha-reductase isozymes. FK143 reduced the testosterone-indu ce increase in the amount of the type 1 mRNA in castrated rat, whereas it did not substantially affect the amount of the type 2 mRNA.