Selective inhibition by secosteroids of 5 alpha-reductase activity in human sex skin fibroblasts.

The effects of 5,10-secoestra-4,5-diene-3,10,17-trione (Compound I) and 5,10-seco-19-norpregna-4,5-diene,3,10,20-trione (Compound II) on the 5 alpha-reductase activity and on the androgen receptors of normal human sex skin fibroblasts were investigated. The Vmax and Km of the transformation of testosterone to 5 alpha-reduced products was 387 pg/microgram DNA/30 min and 234 X 10(-9)M, respectively. When the inhibitors were introduced in the assay, the 5 alpha-reductase activity was markedly reduced, Compound I being a less potent inhibitor than Compound II. At 15 min, the inhibition was greater than at 30 and 60 min. The Ki for Compound I was 1.60 x 10(-6)M with a Vmax of 83 to 553 pg/microgram DNA/30 min. For Compound II, the Ki was 0.53 x 10(-6)M with a Vmax of 70 to 340 pg/microgram DNA/30 min. The inhibition was of the noncompetitive type. Studies with androgen receptors showed that Compound I had a lower affinity for the receptors than Compound II. The ID50 for 3H-DHT and 3H-T for Compound I were 42.9 x 10(-7)M and 8.6 x 10(-7)M, respectively, whereas for Compound II, they were 10.6 x 10(-7)M and 4.8 x 10(-7)M.