Malikova Jana, Brixius-Anderko Simone, Udhane Sameer S, Parween Shaheena, Dick Bernhard, Bernhardt Rita, Pandey Amit V
Pediatric Endocrinology, Diabetology and Metabolism, University Children's Hospital, Inselspital, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland.
Department of Biochemistry, Faculty of Technical and Natural Sciences, Saarland University, 66123 Saarbrücken, Germany.
J Steroid Biochem Mol Biol. 2017 Nov;174:192-200. doi: 10.1016/j.jsbmb.2017.09.007. Epub 2017 Sep 8.
Abiraterone is an inhibitor of CYP17A1 which is used for the treatment of castration resistant prostate cancer. Abiraterone is known to inhibit several drug metabolizing cytochrome P450 enzymes including CYP1A2, CYP2D6, CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP3A5, but its effects on steroid metabolizing P450 enzymes are not clear. In preliminary results, we had observed inhibition of CYP21A2 by 1μM abiraterone. Here we are reporting the effect of abiraterone on activities of CYP21A2 in human adrenal cells as well as with purified recombinant CYP21A2. Cells were treated with varying concentrations of abiraterone for 24h and CYP21A2 activity was measured using [H] 17-hydroxyprogesterone as substrate. Whole steroid profile changes were determined by gas chromatography-mass spectrometry. Binding of abiraterone to purified CYP21A2 protein was measured spectroscopically. Computational docking was used to study the binding and interaction of abiraterone with CYP21A2. Abiraterone caused significant reduction in CYP21A2 activity in assays with cells and an inhibition of CYP21A2 activity was also observed in experiments using recombinant purified proteins. Abiraterone binds to CYP21A2 with an estimated Kd of 6.3μM. These inhibitory effects of abiraterone are at clinically used concentrations. A loss of CYP21A2 activity in combination with reduction of CYP17A1 activities by abiraterone could result in lower cortisol levels and may require monitoring for any potential adverse effects.
阿比特龙是一种CYP17A1抑制剂，用于治疗去势抵抗性前列腺癌。已知阿比特龙可抑制多种药物代谢细胞色素P450酶，包括CYP1A2、CYP2D6、CYP2C8、CYP2C9、CYP2C19、CYP3A4和CYP3A5，但其对类固醇代谢P450酶的影响尚不清楚。在初步结果中，我们观察到1μM阿比特龙可抑制CYP21A2。在此，我们报告阿比特龙对人肾上腺细胞以及纯化的重组CYP21A2中CYP21A2活性的影响。用不同浓度的阿比特龙处理细胞24小时，并以[H] 17-羟孕酮为底物测量CYP21A2活性。通过气相色谱-质谱法测定整个类固醇谱的变化。通过光谱法测量阿比特龙与纯化的CYP21A2蛋白的结合。使用计算对接研究阿比特龙与CYP21A2的结合和相互作用。在细胞实验中，阿比特龙导致CYP21A2活性显著降低，在使用重组纯化蛋白的实验中也观察到CYP21A2活性受到抑制。阿比特龙与CYP21A2结合，估计解离常数（Kd）为6.3μM。阿比特龙的这些抑制作用在临床使用浓度下即可出现。阿比特龙导致CYP21A2活性丧失，同时降低CYP17A1活性，可能会导致皮质醇水平降低，可能需要监测任何潜在的不良反应。
