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

Abstract

Two radioiodinated probes, '%cholesteryl oleate ('251-CO), a derivative of a natural constituent of lipoproteins, and l-(2-chlorophenyl)-1-(4['25I]iodopheny1>2,2-dichloroethane ('%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 '*%CO into rat HDL increased the uptake of '251-C0 by rat adrenal, which was dramatically enhanced when this preparation was administered to animals made hypolipidemic with 4-aminopyrazolo-(3,4)-pyrimidine (CAPP). Acetylation of HDL labeled with '2sI-C0 provided evidence that the observed uptake into the adrenal was via a receptormediated process. In contrast with these results, prior association of '*'I-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 '%CO and '*'I-DDD with rat HDL. These results suggested that '251-C0 was associated with the lipophilic core of HDL, whereas '*'I-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. 0 1985 Academic press, 1~.

High-dose mitotane strategy in adrenocortical carcinoma: prospective analysis of plasma mitotane measurement during the first 3 months of follow-up

“…However, such mechanisms remain to be elucidated. For instance, mitotane is bound to lipoproteins in the plasma (30,31) and access to target tissue such as the brain is dependent on lipoprotein profiles (32). Furthermore, mitotane has been shown to affect lipoprotein profiles by increasing low-density lipoprotein and high-density lipoproteins (28).…”

6-Deoxy-6-[¹³¹I]iodo-<small>L</small>-ascorbic Acid for the <i>in Vivo</i> Study of Ascorbate: Autoradiography, Biodistribution in Normal and Hypolipidemic Rats, and in Tumor-Bearing Nude Mice

“…39) Administration of 4-APP to rats has been reported to induce a marked depletion of cholesterol from the adrenal glands, upregulation of low-density lipoprotein receptors on adrenal cell membranes, [40][41][42] and high plasma adrenocorticotropic hormone (ACTH) levels. 43,44) The rat adrenal uptake of potential adrenal imaging agents such as radioiodinated cholesteryl esters 42,45) and cholesteryl-p-[ 18 F]fluorobenzoate, 35) has been shown to increase when pretreated with 4-APP. Although the function of AsA in the adrenal gland is incompletely understood, the participation of AsA in steroidogenesis has been suggested for a long time.…”

Distribution of toxaphene, DDT, and PCB among lipoprotein fractions in rat and human plasma

“…Factors of primary importance are related to the structure of the lipoprotein fraction (the surface apoproteins and the lipid composition of the lipid core), the abundance of each of the individual lipoprotein fractions in plasma, as well as the type of xenobiotic and its lipophilicity (see also Vomachka et al 1984;Busbee et al 1985;Pohland and Counsell 1985).…”

“…The results of earlier investigations support the view that the binding is of a non-specific nature closely related to the lipophilicity of the compound. Recent studies, however, have indicated that the preference of a lipophilic compound for lipoproteins cannot be explained entirely on the basis of lipid solubility (Vomachka et al 1984;Pohland and Counsell 1985). The associations between xenobiotics and lipoproteins give rise to questions about possible effects of lipoproteins on the tissue uptake of these types of lipophilic compounds, and conversely, the effect of xenobiotics on the metabolism of lipoproteins.…”