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Inhibition of steroid 5 alpha-reductase by specific aliphatic
unsaturated fatty acids.
AUTHOR
Liang T; Liao S
JOURNAL
Journal of Biochemistry, 1992 Jul 15, 285 ( Pt 2):, 557-62
ABSTRACT
Human or rat microsomal 5 alpha-reductase activity, as measured
by enzymatic conversion of testosterone into 5 alpha-dihydrotestosterone
or by binding of a competitive inhibitor, [3H]17 beta-NN-diethulcarbamoyl-4-methyl-4-aza-5
alpha-androstan-3-one ([3H]4-MA) to the reductase, is inhibited
by low concentrations (less than 10 microM) of certain polyunsaturated
fatty acids. The relative inhibitory potencies of unsaturated fatty
acids are, in decreasing order: gamma-linolenic acid greater than
cis-4,7,10,13,16,19-docosahexaenoic acid = cis-6,9,12,15-octatetraenoic
acid = arachidonic acid = alpha-linolenic acid greater than linoleic
acid greater than palmitoleic acid greater than oleic acid greater
than 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 enzymatic assay
correlated well except for elaidic acid and linolelaidic 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 enzymatic assay. gamma-Linolenic acid
had no effect on the activities of two other rat liver microsomal
enzymes: NADH:menadione reductase and glucuronosyl transferase.
gamma-Linolenic acid, the most potent inhibitor tested, decreased
the Vmax. and increased Km values of substrates, NADPH and testosterone,
and promoted dissociation of [3H]4-MA from the microsomal reductase.
gamma-Linolenic acid, but not the corresponding saturated fatty
acid (stearic acid), inhibited the 5 alpha-reductase activity, but
not the 17 beta-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.
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