Pohland R C, Counsell R E
Toxicol Appl Pharmacol. 1985 Jan;77(1):47-57. doi: 10.1016/0041-008x(85)90266-2.
Two radioiodinated probes, 125I-cholesteryl oleate (125I-CO), a derivative of a natural constituent of lipoproteins, and 1-(2-chlorophenyl)-1-(4[125I]iodophenyl)-2,2-dichlorethane (125I-DDD), an analog of the adrenolytic drug o,p'-DDD (mitotane), were selected to study the role of lipoproteins in drug disposition and to examine the ability of these vehicles to direct foreign molecules to specific tissues. In vivo and in vitro techniques were utilized to associate these probes with rat high density lipoproteins (HDL). Tissue distribution studies indicated that prior incorporation of 125I-CO into rat HDL increased the uptake of 125I-CO by rat adrenal, which was dramatically enhanced when this preparation was administered to animals made hypolipidemic with 4-aminopyrazolo(3,4-d)-pyrimidine (4-APP). Acetylation of HDL labeled with 125I-CO provided evidence that the observed uptake into the adrenal was via a receptor-mediated process. In contrast with these results, prior association of 125I-DDD with rat HDL failed to alter the ability of this compound to accumulate in adrenal tissue of normal or hypolipidemic animals. Polyacrylamide gel electrophoresis (PAGE) was utilized to examine the stability of the association of 125I-CO and 125I-DDD with rat HDL. These results suggested that 125I-CO was associated with the lipophilic core of HDL, whereas 125I-DDD appeared to be partially associated with the surface components of HDL. Saturation of surface components with stable o,p'-DDD offered data to suggest that this binding to apoproteins may disrupt the normal receptor-mediated uptake process. These studies indicate that lipoproteins may effect the distribution and tissue uptake of lipophilic compounds and, conversely, lipophilic molecules can effect the metabolic fate of lipoproteins. The overall result is dependent upon the nature of the association of these lipophilic compounds with lipoproteins which is difficult to predict on the basis of molecular structure alone.
选用了两种放射性碘化探针，即脂蛋白天然成分的衍生物125I - 胆固醇油酸酯（125I - CO）和肾上腺溶解药物邻对滴滴滴（米托坦）的类似物1 -（2 - 氯苯基）- 1 -（4 - [125I]碘苯基）- 2,2 - 二氯乙烷（125I - DDD），以研究脂蛋白在药物处置中的作用，并考察这些载体将外来分子导向特定组织的能力。运用体内和体外技术使这些探针与大鼠高密度脂蛋白（HDL）相结合。组织分布研究表明，预先将125I - CO掺入大鼠HDL中会增加大鼠肾上腺对125I - CO的摄取，当将该制剂给予用4 - 氨基吡唑并（3,4 - d）嘧啶（4 - APP）诱导的低脂血症动物时，这种摄取显著增强。对用125I - CO标记的HDL进行乙酰化处理，为观察到的肾上腺摄取是通过受体介导的过程提供了证据。与这些结果相反，预先将125I - DDD与大鼠HDL相结合未能改变该化合物在正常或低脂血症动物肾上腺组织中蓄积的能力。利用聚丙烯酰胺凝胶电泳（PAGE）来检测125I - CO和125I - DDD与大鼠HDL结合的稳定性。这些结果表明，125I - CO与HDL的亲脂核心相结合，而125I - DDD似乎部分与HDL的表面成分相结合。用稳定的邻对滴滴滴使表面成分饱和提供的数据表明，这种与载脂蛋白的结合可能会破坏正常的受体介导的摄取过程。这些研究表明，脂蛋白可能影响亲脂性化合物的分布和组织摄取，反之，亲脂性分子也可能影响脂蛋白的代谢命运。总体结果取决于这些亲脂性化合物与脂蛋白结合的性质，而仅凭分子结构很难预测这种性质。
