5 alpha-reductase-catalyzed conversion of testosterone to dihydrotestosterone is increased in prostatic adenocarcinoma cells: suppression by 15-lipoxygenase metabolites of gamma-linolenic and eicosapentaenoic acids.
Although the androgens, testosterone (T) and its highly active metabolite dihydrotestosterone (DHT) play a role in the development and progression of prostate cancer, the mechanism(s) are unclear. Furthermore, 5 alpha-reductase which catalyze the conversion of T to DHT, has been a target of manipulation in the treatment of prostatic cancer, hence synthetic 5 alpha-reductase activity inhibitors have shown therapeutic promise. To demonstrate that nutrients derived from dietary sources can exert similar therapeutic promise, this study was designed using benign hyperplastic cells (BHC) and malignant tumorigenic cells (MTC) derived from Lobund-Wistar (L-W) rat model of prostatic adenocarcinoma to test the effects of gamma-linolenic acid (GLA), eicosapentaenoic acid (EPA) and their 15-lipoxygenase metabolites on cellular 5 alpha-reductase activity. Our data revealed: (i) that incubation of MTC with [3H]-T resulted in marked conversion to [3H]-DHT when compared to similar incubation with BHC; (ii) that DHT-enhanced activity of 5 alpha-reductase was inhibited 80% by 15S-hydroxyeicosatrienoic acid, the 15-lipoxygenase metabolite of GLA, when compared to 55% by 15S-hydroxyeicosapentaenoic acid, the 15-lipoxygenase metabolite of EPA; and (iii) that their precursor fatty acids, respectively, exerted moderate inhibition. Taken together, the study underscores the biological importance of 15-lipoxygenase metabolites of polyunsaturated fatty acids (PUFAs) in androgen metabolism.
Pham
Hung
H
Department of Dermatology, School of Medicine, University of California at Davis, TB-192, One Shields Avenue, 95616, USA.
Ziboh
Vincent A
VA
D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D002478:Cells, Cultured; D042944:Cholestenone 5 alpha-Reductase; D013196:Dihydrotestosterone / Q000378:metabolism*; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D008297:Male; D010088:Oxidoreductases / Q000378:metabolism*; D011470:Prostatic Hyperplasia / Q000201:enzymology / Q000473:pathology; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013739:Testosterone / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D017965:gamma-Linolenic Acid / Q000494:pharmacology*
D013196:Dihydrotestosterone; D013739:Testosterone; D017965:gamma-Linolenic Acid; D015118:Eicosapentaenoic Acid; D010088:Oxidoreductases; D001093:Arachidonate 15-Lipoxygenase; D042944:Cholestenone 5 alpha-Reductase