Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, PR China.
Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, PR China.
J Steroid Biochem Mol Biol. 2022 Jul;221:106117. doi: 10.1016/j.jsbmb.2022.106117. Epub 2022 Apr 30.
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.
雄激素的积累介导了前列腺生长的改变，并且已成为良性前列腺增生（BPH）的一个重要因素。二氢睾酮（DHT）是最有效的天然雄激素，与雄激素受体（AR）结合并调节前列腺生长。已经开发出许多 DHT 合成抑制剂来降低 DHT 水平，并用于治疗前列腺疾病。然而，针对消除 DHT 的治疗方法仍然有限。DHT 在前列腺中被 UDP-葡糖醛酸基转移酶 2B（UGT2B）代谢，并转化为无活性产物。在这项研究中，我们分析并证明了 naftopidil（NAF）的两种对映异构体，一种 α1D/1A-肾上腺素能受体阻滞剂，在 BPH 大鼠前列腺模型以及人前列腺细胞 BPH-1 中诱导 UGT2B 的表达和活性。NAF 对映异构体降低了前列腺内和细胞内 DHT 水平，从而促进细胞凋亡。此外，用 siRNA UGT2B15 转染进行的测定表明，UGT2B15 在介导 NAF 对映异构体的作用中起重要作用。UGT2B15 介导了 NAF 对映异构体对 AR 和 PSA 表达的抑制。数据表明，NAF 对映异构体上调 UGT2B15 的机制可能与 AR 拮抗剂和 5α-还原酶抑制剂不同。总之，我们的结果表明，NAF 对映异构体可能是潜在的新型 UGT2B15 调节剂，可加速 DHT 的消除并促进 BPH-1 细胞的凋亡。这项研究可以帮助扩大 NAF 的临床应用，并支持开发针对消除雄激素的新治疗策略，以治疗 BPH 和其他雄激素敏感疾病。
