Inhibition of type 1 and type 2 5α-reductase activity by free fatty acids, active ingredients of permixon®

In different cell systems, the lipido-sterolic extract of Serenoa repens (LSESr, Permixon((R))) inhibits both type 1 and type 2 5alpha-reductase activity (5alphaR1 and 5alphaR2). LSESr is mainly constituted of fatty acids (90 +/- 5%) essentially as free fatty acids (80%). Among these free fatty acids, the main components are oleic and lauric acids which represent 65% and linoleic and myristic acids 15%. To evaluate the inhibitory effect of the different components of LSESr on 5alphaR1 or %R2 activity, the corresponding type 1 and type 2 human genes have been cloned and expressed in the baculovirus-directed insect cell expression system Sf9. The cells were incubated at pH 5.5 (5alphaR2) and pH 7.4 (5alphaR1) with 1 or 3 nM testosterone in presence or absence of various concentrations of LSESr or of its different components. Dihydrotestosterone formation was measured with an automatic system combining HPLC and an on-line radiodetector. The inhibition of 5alphaR1 and 5alphaR2 activity was only observed with free fatty acids: esterified fatty acids, alcohols as well as sterols assayed were inactive. A specificity of the fatty acids in 5alphaR1 or 5alphaR2 inhibition has been found. Long unsaturated chains (oleic and linolenic) were active (IC50 = 4 +/- 2 and 13 +/- 3 mug/ml, respectively) on 5alphaR1 but to a much lesser extent (IC50 > 100 and 35 +/- 21 mug/ml, respectively) on 5alphaR2. Palmitic and stearic acids were inactive on the two isoforms. Lauric acid was active on 5alphaR1 (IC50 = 17 +/- 3 mug/ml) and 5alphaR2 (IC50 = 19 +/- 9 mug/ml). The inhibitory activity of myristic acid was evaluated on 5alphaR2 only and found active on this isoform (IC50 = 4 +/- 2 mug/ml). The dual inhibitory activity of LSESr on 5alpha-reductase type 1 and type 2 can be attributed to its high content in free fatty acids. (C) 2002 Published by Elsevier Science Ltd.