Inhibition of steroid 5α-reductase by specific aliphatic unsaturated fatty acids

Abstract

Human or rat microsomal 5α-reductase activity, as measured by enzymic conversion of testosterone into 5α-dihydrotestosterone or by binding of a competitive inhibitor, [3H]17β,6-NN-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one ([3H]4-MA) to the reductase, is inhibited by low concentrations (< 10 μM) of certain polyunsaturated fatty acids. The relative inhibitory potencies of unsaturated ratty acids are, in decreasing order: γ-linolenic acid > cis-4,7,10,13,16,19-docosahexaenoic acid = cis-6,9,12,15-octatetraenoic acid = arachidonic acid = α-linolenic acid > linoleic acid > palmitoleic acid > oleic acid > myristoleic acid. Other unsaturated fatty acids such as undecylenic acid, erucic acid and nervonic acid, are inactive. The methyl esters and alcohol analogues of these compounds, glycerols, phospholipids, saturated fatty acids, retinoids and carotenes were inactive even at 0.2 mM. The results of the binding assay and the enzymic assay correlated well except for elaidic acid and linolclaidic acid, the trans isomers of oleic acid and linoleic acid respectively, which were much less active than their Cis isomers in the binding assay but were as potent in the enzymic assay. γ-Linolenic acid had no effect on the activities of two other rat liver microsomal enzymes: NADH:menadione reductase and glucuronosyl transferase. γ-Linolenic acid, the most potent inhibitor tested, decreased the V(max.) and increased K(m) values of substrates, NADPH and testosterone, and promoted dissociation of [3H]4-MA from thc microsomal reductase. γ-Linolenic acid, but not the corresponding saturated fatty acid (stearic acid), inhibited the 5α-reductase activity, but not the 17β-dehydrogenase activity, of human prostate cancer cells in culture. These results suggest that unsaturated fatty acids may play an important role in regulating androgen action in target cells.