Membrane Protein Research Group, Institute of Enzymology, RCNS, H-1117, Budapest, Magyar tudósok krt. 2, Hungary.
Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720, Szeged, Hungary.
J Steroid Biochem Mol Biol. 2020 Jun;200:105652. doi: 10.1016/j.jsbmb.2020.105652. Epub 2020 Mar 6.
Human OATP2B1 encoded by the SLCO2B1 gene is a multispecific transporter mediating the cellular uptake of large, organic molecules, including hormones, prostaglandins and bile acids. OATP2B1 is ubiquitously expressed in the human body, with highest expression levels in pharmacologically relevant barriers, like enterocytes, hepatocytes and endothelial cells of the blood-brain-barrier. In addition to its endogenous substrates, OATP2B1 also recognizes clinically applied drugs, such as statins, antivirals, antihistamines and chemotherapeutic agents and influences their pharmacokinetics. On the other hand, OATP2B1 is also overexpressed in various tumors. Considering that elevated hormone uptake by OATP2B1 results in increased cell proliferation of hormone dependent tumors (e.g. breast or prostate), inhibition of OATP2B1 can be a good strategy to inhibit the growth of these tumors. 13-epiestrones represent a potential novel strategy in the treatment of hormone dependent cancers by the suppression of local estrogen production due to the inhibition of the key enzyme of estrone metabolism, 17ß-hydroxysteroid-dehydrogenase type 1 (HSD17ß1). Recently, we have demonstrated that various phosphonated 13-epiestrones are dual inhibitors also suppressing OATP2B1 function. In order to gain better insights into the molecular determinants of OATP2B1 13-epiestrone interaction we investigated the effect of C-2 and C-4 halogen or phenylalkynyl modified epiestrones on OATP2B1 transport function. Potent inhibitors (with EC values in the low micromolar range) as well as non-inhibitors of OATP2B1 function were identified. Based on the structure-activity relationship (SAR) of the various 13-epiestrone derivatives we could define structural elements important for OATP2B1 inhibition. Our results may help to understand the drug/inhibitor interaction profile of OATP2B1, and also may be a useful strategy to block steroid hormone entry into tumors.
人源有机阴离子转运多肽 2B1（SLCO2B1 基因编码）是一种多特异性转运体，介导包括激素、前列腺素和胆汁酸在内的大有机分子的细胞摄取。OATP2B1 在人体中广泛表达，在具有药理学相关性的屏障中表达水平最高，如肠细胞、肝细胞和血脑屏障的内皮细胞。除了其内源性底物外，OATP2B1 还识别临床应用的药物，如他汀类药物、抗病毒药物、抗组胺药和化疗药物，并影响它们的药代动力学。另一方面，OATP2B1 在各种肿瘤中也过度表达。由于 OATP2B1 摄取激素会导致激素依赖性肿瘤（如乳腺癌或前列腺癌）的细胞增殖增加，因此抑制 OATP2B1 可能是抑制这些肿瘤生长的一种好策略。13-表雌酮通过抑制关键酶 17β-羟类固醇脱氢酶 1（HSD17β1）来抑制局部雌激素产生，代表了一种治疗激素依赖性癌症的潜在新策略。最近，我们已经证明，各种膦酸 13-表雌酮也是双重抑制剂，也能抑制 OATP2B1 功能。为了更好地了解 OATP2B1 与 13-表雌酮相互作用的分子决定因素，我们研究了 C-2 和 C-4 卤代或苯乙炔基修饰的表雌酮对 OATP2B1 转运功能的影响。确定了强效抑制剂（EC 值在低微摩尔范围内）和 OATP2B1 功能的非抑制剂。基于各种 13-表雌酮衍生物的构效关系（SAR），我们可以确定对 OATP2B1 抑制作用重要的结构要素。我们的研究结果可能有助于了解 OATP2B1 的药物/抑制剂相互作用谱，也可能是阻止甾体激素进入肿瘤的有用策略。
