Naftopidil enantiomers suppress androgen accumulation and induce cell apoptosis via the UDP-glucuronosyltransferase 2B15 in benign prostate hyperplasia. Issue 221 (July 2022)

• Record Type: Journal Article
• Authors: Zhan, Haoxin; Zhang, Silin; Li, Lirong; Chen, Zikai; Cai, Yi; Huang, Junjun; Wu, Dan; Huang, Biyun; Wu, Bo; Liu, Xiawen
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 221(2022)
• Publication Date: 2022-07
• Subjects: Androgen elimination -- Dihydrotestosterone (DHT) -- UGT2B15 -- Naftopidil enantiomer -- Benign prostate hyperplasia (BPH); Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2022.106117
• Languages: English
• ISSNs: 0960-0760

Abstract

Abstract: Accumulation of androgens mediate alterations in prostate growth and has emerged as an essential factor in benign prostate hyperplasia (BPH). Dihydrotestosterone (DHT), the most potent natural androgen, binds to androgen receptors (AR) and regulates the prostate growth. Many inhibitors of DHT synthesis have been developed to reduce DHT levels and used in the treatment of prostate diseases. However, therapies targeting the elimination of the DHT remain limited. The DHT in prostate is metabolized by UDP-glucuronosyltransferase 2B (UGT2B) and transforms into inactive products. In this study, we analyzed and demonstrated that two enantiomers of naftopidil (NAF), an α1D/1A-adrenoceptor blocker, induced expression and activity of UGT2B in BPH rat prostate models as well as UGT2B15 in human prostate cells, BPH-1. The NAF enantiomers reduced intraprostatic and intracellular DHT levels, thus promoting cell apoptosis. Besides, assays with siRNA UGT2B15 transfection showed that UGT2B15 played an essential role in mediating the effects of the NAF enantiomers. The UGT2B15 mediated the inhibition of AR and PSA expression by NAF enantiomers. The data showed that the mechanism of upregulating UGT2B15 by the NAF enantiomers might differ from that of AR antagonists and 5α-reductase inhibitors. Together, our results demonstrated that NAF enantiomers could be potential and novel UGT2B15 regulators, which accelerated the DHT elimination and promoted apoptosis of BPH-1 cells. This study could help expand the clinical application of NAF and support the development of new therapeutic strategies targeting the elimination of androgens for the treatment of BPH and other androgen-sensitive diseases. Graphical Abstract: ga1 Highlights: NAF is a potential and novel UGT2B15 regulator. NAF inhibits DHT accumulation and induces apoptosis targeting on UGT2B15. S(-)-NAF is a prior enantiomer. The mechanisms of NAF regulating UGT2B15 is different differs from that of AR antagonists and 5-ARIs.