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Licensed Unlicensed Requires Authentication Published by De Gruyter August 1, 2010

Human type 3 5α-reductase is expressed in peripheral tissues at higher levels than types 1 and 2 and its activity is potently inhibited by finasteride and dutasteride

Kazutoshi Yamana, Fernand Labrie and Van Luu-The

Abstract

5α-Reductases are crucial enzymes involved in the biosynthesis of dihydrotestosterone, the most potent natural androgen. To date, three types of 5α-reductases, chronologically named types 1, 2 and 3 5α-reductases (SRD5a-1, 2 and 3) have been described. In the present paper, we characterized the activity and compared the mRNA expression levels of SRD5a-3 with those of SRD5a-1 and 2 in various human tissues, and determined its sensitivity to finasteride and dutasteride. We have established HEK-293 cell line that stably expressed SRD5a-3 for studying its activity and the inhibitory effect of finasteride, using [14C]labeled steroids. mRNA expression levels were quantified using real-time PCR in many male and female human tissues including the prostate, adipose tissue, mammary gland, as well as breast and prostate cancer cell lines. Incubation of HEK-SRD5a-3 cells with [14C]4-androstenedione and [14C]testosterone allowed us to show that SRD5a-3 can catalyze very efficiently both substrates 4-androstenedione and testosterone into 5α-androstanedione and dihydrotestosterone, respectively. We observed that the affinity of the enzyme for 4-androstenedione is higher than for testosterone. The activity of SRD5a-3 and SRD5a-2 are similarly sensitive to finasteride, whereas dutasteride is a much more potent inhibitor of SRD5a-3 than SRD5a-2. Tissue distribution analysis shows that SRD5a-3 mRNA expression levels are higher than those of SRD5a-1 and SRD5a-2 in 20 analyzed tissues. In particular, it is highly expressed in the skin, brain, mammary gland and breast cancer cell lines, thus suggesting that SRD5a-3 could play an important role in the production of androgens in these and other peripheral tissues.


Corresponding author: Dr. Van Luu-The, Research Center in Molecular Endocrinology, Oncology and Human Genomics (CREMOGH) and Department of Molecular Medicine, Faculty of Medicine, Laval University and the Laval University Hospital Research Center (CRCHUL), 2705 Laurier Boulevard, T3–52, Quebec City, QC, G1V 4G2, Canada Phone: +1-418-654-2296, Fax: +1-418-654-2761,

Received: 2010-4-12
Accepted: 2010-5-17
Published Online: 2010-08-01
Published in Print: 2010-08-01

©2010 by Walter de Gruyter Berlin New York

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