STRUCTURE-DEPENDENT, COMPETITIVE INTERACTION OF HYDROXY-POLYCHLOROBIPHENYLS, HYDROXY-DIBENZO-P-DIOXINS AND HYDROXY-DIBENZOFURANS WITH HUMAN TRANSTHYRETIN
STRUCTURE-DEPENDENT, COMPETITIVE INTERACTION OF HYDROXY-POLYCHLOROBIPHENYLS, HYDROXY-DIBENZO-P-DIOXINS AND HYDROXY-DIBENZOFURANS WITH HUMAN TRANSTHYRETIN
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DOI：
10.1016/0009-2797(93)90081-9
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发表时间：
1993-07-01
影响因子：
5.1
通讯作者：
BROUWER, A
中科院分区：
文献类型：
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作者：
LANS, MC;KLASSONWEHLER, E;BROUWER, A
本实验室先前的研究结果表明，在大鼠体内和体外，3，3 '，4，4'-四氯联苯的羟基化代谢物与血浆甲状腺激素转运蛋白转甲状腺素蛋白（TTR）之间存在特异性和竞争性相互作用。在本研究中，与甲状腺素（T4）的TTR结合竞争的结构要求进行了更详细的研究。几个羟基化多氯联苯（PCBs），二苯并二恶英（PCDDs）和二苯并呋喃（PCDFs）进行了测试，在体外竞争性结合试验，使用纯化的人TTR和[I-125]T4作为可置换的放射性配体。所有羟基化PCB，但不是单一的PCB测试，竞争性取代[I-125]T4从TTR与差异的效力。在羟基化多氯联苯同系物中观察到最高的竞争性结合效力，其中羟基在Meta位或帕拉被取代，一个或多个氯原子在一个或两个芳环上的羟基附近被取代（IC 50范围为6.5 - 25 nM; K（a）范围：0.78 - 3.95 x 10（8）M-1）。所有Meta或帕拉羟基化多氯联苯的相对效力高于生理配体T4的相对效力（相对效力范围：与T4相比为3.5 - 13.6）。邻位氯取代和非邻位氯取代羟基多氯联苯同系物之间的TTR-T4竞争性结合能力没有明显区别。在所测试的有限数量的羟基化多氯二苯并对二恶英和多氯二苯并呋喃之间观察到TTR-T4结合竞争效力的显著差异。羟基-多氯二苯并对二恶英和多氯二苯并呋喃（在羟基附近有氯取代），即7-OH-2，3，8-三氯二苯并对二恶英、2-OH-1，3，7，8-四氯二苯并对二恶英和3-OH-2，6，7，8-四氯二苯并呋喃，均显示出类似或更高的相对结合能力，即分别比T4高1、4.4和4.5倍。2-OH-7，8-二氯二苯并呋喃、8-OH-2，3，4-三氯二苯并呋喃和8-OH-2，3-二氯二苯并-p-二恶英（不含邻近OH基团的氯取代）未观察到可检测的[I-125]T4置换。这些结果表明，羟基-多氯联苯，-多氯二苯并对二恶英和-多氯二苯并呋喃代谢物和生理配体T4之间TTR结合的结构要求有着深刻的相似性，例如帕拉羟基的卤素取代，而平面性似乎并不影响配体结合的效力。
Previous results from our laboratory indicated specific and competitive interactions of hydroxylated metabolites of 3,3',4,4'-tetrachlorobiphenyl with the plasma thyroid hormone transport protein, transthyretin (TTR), in rats in vivo and with human TTR in vitro. In the present study the structural requirements for competition with thyroxine (T4) for TTR-binding were investigated in more detail. Several hydroxylated polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) were tested in an in vitro competitive binding assay, using purified human TTR and [I-125]T4 as a displaceable radioligand. All hydroxylated PCBs, but not the single PCB tested, competitively displaced [I-125]T4 from TTR with differential potency. The highest competitive binding potency was observed for hydroxylated PCB congeners with the hydroxygroup substituted on meta or para positions and one or more chlorine atoms substituted adjacent to the hydroxy group on either or both aromatic rings (IC50 range 6.5 - 25 nM; K(a) range: 0.78 - 3.95 x 10(8) M-1). The relative potency of all meta or para hydroxylated PCBs was higher than that of the physiological ligand, T4 (relative potency range: 3.5 - 13.6 compared to T4). There were no marked distinctions in TTR-T4 competitive binding potencies between the ortho- and non-ortho-chlorine substituted hydroxy-PCB congeners tested. Marked differences in TTR-T4 binding competition potency were observed between the limited number of hydroxylated PCDDs and PCDFs tested. The hydroxy-PCDD/Fs, with chlorine substitution adjacent to the hydroxy-group, i.e. 7-OH-2,3,8-trichlorodibenzo-p-dioxin, 2-OH-1,3,7,8-tetrachlorodibenzo-p-dioxin and 3-OH-2,6,7,8-tetrachlorodibenzofuran, all showed a similar or higher relative binding potency, i.e. 1, 4.4 and 4.5 times higher, respectively, than T4. No detectable [I-125]T4 displacement was observed with 2-OH-7,8-dichlorodibenzofuran, 8-OH-2,3,4-trichlorodibenzofuran and 8-OH-2,3-dichlorodibenzo-p-dioxin, which did not contain chlorine substitution adjacent to the OH-group. These results indicate a profound similarity in structural requirements for TTR binding between hydroxy-PCB, -PCDD and -PCDF metabolites and the physiological ligand, T4, e.g. halogen substitution adjacent to the para hydroxy group, while planarity does not seem to influence the ligand-binding potency.