Inhibition of type 1 and type 2 5alpha-reductase activity by free fatty acids, active ingredients of Permixon.
In different cell systems, the lipido-sterolic extract of Serenoa repens (LSESr, Permixon 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 5alphaR2 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 3nM 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 (IC(50)=4+/-2 and 13+/-3 microg/ml, respectively) on 5alphaR1 but to a much lesser extent (IC(50)>100 and 35+/-21 microg/ml, respectively) on 5alphaR2. Palmitic and stearic acids were inactive on the two isoforms. Lauric acid was active on 5alphaR1 (IC(50)=17+/-3 microg/ml) and 5alphaR2 (IC(50)=19+/-9 microg/ml). The inhibitory activity of myristic acid was evaluated on 5alphaR2 only and found active on this isoform (IC(50)=4+/-2 microg/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.
Raynaud
Jean Pierre
JP
D.R.I.T.T., Université Pierre et Marie Curie, 4 Place Jussieu, Paris, France. jean-pierre.raynaud@admp6.jussieu.fr
Cousse
Henri
H
Martin
Pierre Marie
PM
D000726:Androgen Antagonists / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D042944:Cholestenone 5 alpha-Reductase; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D005233:Fatty Alcohols / Q000494:pharmacology; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D028024:Serenoa; D012855:Sitosterols / Q000494:pharmacology; D024505:Tocopherols / Q000494:pharmacology
D000726:Androgen Antagonists; D005230:Fatty Acids, Nonesterified; D005233:Fatty Alcohols; D000960:Hypolipidemic Agents; D007527:Isoenzymes; D010936:Plant Extracts; D012855:Sitosterols; C025473:gamma-sitosterol; C529236:docosanol; D010088:Oxidoreductases; D042944:Cholestenone 5 alpha-Reductase; C040972:saw palmetto extract; D024505:Tocopherols