The role of high density lipoproteins in the biodistribution of two radioiodinated probes in the rat

Abstract

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-dichloroethane (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 suface 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.