Abstract：
Cytochrome P450 enzymes (CYPs) play a crucial role in the metabolism and synthesis of various compound classes. While drug-metabolizing CYP enzymes are frequently investigated as anti-targets, the inhibition of CYP enzymes involved in adrenal steroidogenesis is not well studied. The steroidogenic enzyme CYP17A1 is a dual-function enzyme catalyzing hydroxylase and lyase reactions relevant for the biosynthesis of adrenal glucocorticoids and androgens. Inhibition of CYP17A1-hydroxylase leads to pseudohyperaldosteronism with subsequent excessive mineralocorticoid receptor activation, hypertension and hypokalemia. In contrast, specific inhibition of the lyase function might be beneficial for the treatment of prostate cancer by decreasing adrenal androgen levels. This study combined in silico and in vitro methods to identify drugs inhibiting CYP17A1. The most potent CYP17A1 inhibitors identified are serdemetan, mocetinostat, nolatrexed, liarozole, and talarozole. While some of these drugs are currently under investigation for the treatment of various cancers, their potential for the treatment of prostate cancer is yet to be explored. The DrugBank database was screened for CYP17A1 inhibitors, to increase the awareness for the risk of drug-induced pseudohyperaldosteronism and to highlight drugs so far unknown for their potential to cause side effects resulting from CYP17A1 inhibition.
摘要：
细胞色素P450酶（CYP）在各种化合物的代谢和合成中起着至关重要的作用。虽然药物代谢CYP酶经常被研究作为抗靶标，与肾上腺类固醇生成有关的CYP酶的抑制作用尚未得到充分研究。类固醇生成酶CYP17A1是催化与肾上腺糖皮质激素和雄激素的生物合成相关的羟化酶和裂解酶反应的双功能酶。抑制CYP17A1-羟化酶会导致假性醛固酮增多症，随后会导致盐皮质激素受体过度激活，高血压和低钾血症。相比之下,特异性抑制裂解酶功能可能通过降低肾上腺雄激素水平对前列腺癌的治疗有益.本研究结合计算机和体外方法鉴定抑制CYP17A1的药物。鉴定出的最有效的CYP17A1抑制剂是serdemetan，莫西诺他,诺拉曲塞,利罗唑,还有talarozole.虽然其中一些药物目前正在研究用于治疗各种癌症，它们治疗前列腺癌的潜力还有待探索。DrugBank数据库筛选了CYP17A1抑制剂，提高对药物诱导的假性醛固酮增多症风险的认识，并强调迄今为止未知的药物可能引起CYP17A1抑制引起的副作用。
