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  • Human type 3 3[alpha]-hydroxysteroid dehydrogenase (aldo-keto reductase 1C2) andandrogen metabolism in prostate cells
    Lanišnik-Rižner, Tea ...
    Human aldo-keto reductases (AKRs) of the AKR.IC subfamily function in vitro as3-keto-, 17-keto-, and 20-ketosteroid reductases or as 3alpha-, 17beta-, and20alpha-hydroxysteroid oxidases. These AKRs ... can convert potent sex hormones(androgens, estrogens, and progestins) into their cognate inactive metabolites or vice versa. By controlling local ligand concentration AKRs may regulate steroid hormone action at the prereceptor level. AKR1C2 is expressed in prostate, and in oitro it will catalyze the nicotinamide adenine dinucleotide (NAD+)dependent oxidation of 3alpha-androstanediol (3alpha-diol) to 5alphadihydrotestosterone (5a-DHT). This reaction is potently inhibited by reduced NAD phosphate (NADPH), indicating that the NAD+: NADPH ratio in cells will determine whether AKR1C2 makes 5a-DHT. In transient COS-1-AKR1C2 and in stable PC-3-AKR1C2 transfectants, 5alpha-DHT was reduced by AKR1C2. However, the transfected AKR1C2 oxidase activity was insufficient to surmount the endogenous 17beta-hydroxy steroid dehydrogenase (17beta-HSD) activity, which eliminated 3a-diol as androsterone. PC-3 cells expressed retinol dehydrogenase/3alpha-HSD and 11-cis-retinol dehydrogenase, but these endogenous enzymes did not oxidize 3alpha-diol to 5alpha-DHT. In stable LNCaP-AKR1C2 transfectants, AKR1C2 did not alter androgen metabolism due to a high rate of glucuronidation. In primary cultures of epithelial cells, high levels of AKR1C2 transcripts were detected in prostate cancer, but not in cells from normal prostate. Thus, in prostate cells AKR1C2 acts as a 3-ketosteroid reductase to eliminate 5alpha-DHT and prevents activation of theandrogen receptor. AKR1C2 does not act as an oxidase due to either potent product inhibition by NADPH or because it cannot surmount the oxidative 17beta-HSD present. Neither AKR1C2, retinol dehydrogenase/3alpha-HSD nor I1cis-retinol dehydrogenase is a source of 5alpha-DHT in PC-3 cells.
    Vir: Endocrinology. - ISSN 0013-7227 (Letn. 144, št. 7, 2003, str. 2922-2932)
    Vrsta gradiva - članek, sestavni del
    Leto - 2003
    Jezik - angleški
    COBISS.SI-ID - 16395225
vir: Endocrinology. - ISSN 0013-7227 (Letn. 144, št. 7, 2003, str. 2922-2932)
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