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 EC50 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.

中文翻译：

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基于与人有机阴离子运输多肽OATP2B1相互作用的13-表观异构体的结构解剖。

SLCO2B1基因编码的人OATP2B1是一种多特异性转运蛋白，介导细胞对大型有机分子（包括激素，前列腺素和胆汁酸）的摄取。OATP2B1在人体中普遍表达，在药理学相关的屏障（如肠细胞，肝细胞和血脑屏障的内皮细胞）中具有最高的表达水平。除了其内源性底物，OATP2B1还识别临床应用的药物，例如他汀类药物，抗病毒药，抗组胺药和化学治疗剂，并影响其药代动力学。另一方面，OATP2B1在各种肿瘤中也过表达。考虑到OATP2B1的激素摄取增加会导致激素依赖性肿瘤（例如乳腺癌或前列腺癌）的细胞增殖增加，抑制OATP2B1可能是抑制这些肿瘤生长的好策略。13-表观酮类由于抑制雌激素代谢的关键酶1β-羟基类固醇脱氢酶1型（HSD17ß1）而抑制局部雌激素的产生，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，各种磷酸化13-表观电子是双重抑制剂，它们也抑制OATP2B1功能。为了更好地了解OATP2B1 13-电子相互作用的分子决定因素，我们研究了C-2和C-4卤素或苯基炔基修饰的雌酮对OATP2B1转运功能的影响。确定了有效的抑制剂（EC50值在低微摩尔范围内）以及OATP2B1功能的非抑制剂。基于各种13-表观电子衍生物的结构-活性关系（SAR），我们可以定义对OATP2B1抑制重要的结构元素。我们的结果可能有助于了解OATP2B1的药物/抑制剂相互作用，也可能是阻止类固醇激素进入肿瘤的有用策略。