New frontiers in androgen biosynthesis and metabolism.
New frontiers in androgen biosynthesis and metabolism.
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DOI：
10.1097/med.0b013e3283381a31
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发表时间：
2010-06
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--
通讯作者：
Penning TM
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作者：
Penning TM
总结外周组织（如肝脏和前列腺）雄激素生物合成和代谢的最新进展，以及如何利用这些进展进行治疗。人类肝脏催化循环睾酮（T）的还原，产生四种立体异构的四氢类固醇。最近的进展已经分配负责这些反应的酶，并阐明了它们的结构生物学。数据还表明，对于5α-二氢睾酮（5α-DHT），结合反应（II相）可能先于甾酮还原反应（I相）。前列腺是老年男性前列腺增生和前列腺癌的高发部位。虽然局部雄激素生物合成在这些疾病中的重要性是公认的，但最近的进展已经确定了调节配体进入雄激素受体的酶; 5α-DHT的“后门途径”，不需要T作为中间体;以及发现去势抵抗性前列腺癌已经经历了对雄激素剥夺的适应性反应，涉及肿瘤内T和5α-DHT生物合成，可使用（CYP 17-羟化酶/17，20-裂解酶）、醛酮还原酶1C 3和1型和2型5α-还原酶抑制剂靶向。已经鉴定了负责肝和前列腺中雄激素的生物合成和代谢的酶同工型，并且可以在治疗上靶向那些负责去势抵抗性前列腺癌中雄激素的生物合成的酶同工型。
To summarize recent advances in androgen biosynthesis and metabolism in peripheral tissues (e.g. liver and prostate) and how these can be exploited therapeutically. Human liver catalyzes the reduction of circulating testosterone (T) to yield four stereoisomeric tetrahydrosteroids. Recent advances have assigned the enzymes responsible for these reactions and elucidated their structural biology. Data also suggests that for 5α-dihydrotestosterone (5α-DHT), conjugation reactions (phase II) may precede ketosteroid reduction (phase I) reactions. Human prostate is the site of benign prostatic hyperplasia and prostate cancer which occur in the aging male. While the importance of local androgen biosynthesis in these diseases is accepted, recent advances have identified enzymes that regulate ligand access to the androgen receptor; a “backdoor pathway” to 5α-DHT that does not require T acting as an intermediate; and the finding that castrate resistant prostate cancer has undergone an adaptive response to androgen deprivation, which involves intra-tumoral T and 5α-DHT biosynthesis that can be targeted using inhibitors of (CYP17-hydroxylase/17,20-lyase), aldo-keto reductase 1C3, and 5α-reductase type 1 and type 2. Enzyme isoforms responsible for the biosynthesis and metabolism of androgens in liver and prostate have been identified and those responsible for the biosynthesis of androgens in castrate resistant prostate cancer can be therapeutically targeted.