STUDY A: Growth suppression of hamster flank organs by topical application of gamma-linolenic and other fatty acid inhibitors of 5 alpha-reductase.

AUTHOR
Liang T; Liao S

JOURNAL
Journal of Investigational Dermatology: 1997 Aug; 109 (2): 152-7

ABSTRACT
Certain unsaturated aliphatic fatty acids, such as gamma-linolenic acid, inhibit 5alpha-reductase activity in vitro and in vivo. Hamster flank organ growth, as measured by the increase in the area of pigmented macule, is dependent on androgen. When one of the paired flank organs of a castrated hamster was treated topically with testosterone, the treated organ, but not the contralateral flank organ, became larger and darker. Topical application of gamma-linolenic acid to the testosterone-treated flank organ suppressed this testosterone effect. Other fatty acids that were not inhibitors of 5alpha-reductases were not active. Topical treatment of hamster flank organs with 5alpha-dihydrotestosterone also stimulated the growth of the organ. This 5alpha-dihydrotestosterone-dependent activity, however, was not significantly affected by gamma-linolenic acid, suggesting that flank organ growth was dependent on 5alpha-dihydrotestosterone and that gamma-linolenic acid acted by inhibiting 5alpha-reductase. With intact male hamsters, the endogenous androgen-dependent growth of flank organs is also suppressed by topical treatment with gamma-linolenic acid. The effect of gamma-linolenic acid is localized at the site of its application; topical application of gamma-linolenic acid did not affect the androgen-dependent growth of other organs such as testis, epididymis, seminal vesicle, and prostate. gamma-Linolenic acid, with low toxicity and absence of systemic effect, therefore may be potentially useful for treatment of androgen-dependent skin disorders.

Gamma Linolenic Acid and Alpha Linolenic Acid

STUDY B: Androgen action: molecular mechanism and medical application.

AUTHOR
Liao S

JOURNAL
Journal of Formos Medical Association: 1994 Sep; 93 (9): 741-51

ABSTRACT
Androgen action in many organs, such as prostate and skin, is dependent on the conversion of testosterone by 5 alpha-reductase to 5 alpha-dihydrotestosterone. 5 alpha-Dihydrotestosterone then binds to the androgen receptor to regulate specific gene expression. Inhibitors of 5 alpha-reductase are useful for the selective treatment of prostatic cancer, benign prostate hyperplasia, acne, baldness and female hirsuitism, without affecting spermatogenesis, sexual behavior and smooth muscle growth, that do not require the conversion of testosterone to 5 alpha-dihydrotestosterone. Certain unsaturated fatty acids, such as gamma-linolenic acid, are potent 5 alpha-reductase inhibitors, suggesting a linkage between unsaturated fatty acids and androgen action. Mutations in androgen receptor genes are responsible for many cases of androgen-insensitivity. In some prostate cancer cells, some antiandrogens may act like androgens in stimulating the proliferation of the cancer cells because these antiandrogens can bind to a mutated androgen receptor and transactivate target genes. Prostate cancers are usually androgen-dependent initially but can lose dependency and responsiveness. Tumor cells which are resistant to endocrine therapy ultimately proliferate. Androgen-independent or androgen-repressive cells can arise from androgen-sensitive prostate cancer cells by changes in specific gene expression over time in a clonal isolate. This change in androgen responsiveness was accompanied by a change in androgen receptor expression and transcriptional activity as well as expression of some oncogenes.

Gamma Linolenic Acid and Alpha Linolenic Acid

STUDY C: 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.