Liver membranes from young beagle dogs were found to possess binding sites that resemble the low density lipo- protein (LDL) receptors originally described in cultured human fibroblasts. Treatment of the dogs with colestipol (a bile acid se- questrant) and mevinolin (a cholesterol synthesis inhibitor) pro- duced a 3-fold increase in LDL binding activity. This increase cor- related with a 2-fold increase in the fractional catabolic rate for intravenously administered human or canine "LI-labeled LDL, suggesting that the increased hepatic receptors were responsible for the enhanced clearance of LDL from plasma. The hepatic lipo- protein receptors of control and drug-treated dogs resembled hu- man fibroblast LDL receptors in that they bound apoprotein E- containing lipoproteins, such as very low density lipoproteins and a subfraction of high density lipoproteins (HDL ), with 10-fold higher affinity than the apoprotein B-containing lipoprotein LDL; failed to bind canine HDL and human HDL3 which are devoid of apoproteins B and E; failed to bind methylated LDL; required cal- cium; and were destroyed by Pronase. Treatment of dogs with mevinolin not only increased the fractional catabolic rate for LDL but also reduced the synthetic rate for the lipoprotein. The current data suggest that the liver of dogs contains functional LDL recep- tors that are susceptible to metabolic regulation and that a drug- induced increase in the activity of these receptors can contribute to a lowering of plasma levels of LDL-cholesterol.

Regulatory role for hepatic low density lipoprotein receptors in vivo in the dog (cholesterol synthesis inhibitor/mevinolin/bile acid sequestrant/colestipol/catabolism of plasma lipoproteins)

https://febs.onlinelibrary.wiley.com/doi/epdf/10.1016/j.febslet.2006.08.061

Drug-induced phospholipidosis.

Numerous drugs containing a cationic amphiphilic structure are capable of inducing phospholipidosis in cells under conditions of in vivo administration or ex vivo incubation. The principal characteristics of this condition include the reversible accumulation of polar phospholipids in association with the development of unicentric or multicentric lamellated bodies within cells. There is an abundance of data providing an understanding of potential mechanisms for the induction of phospholipidosis; however, the process is likely to be complex and may differ from one drug to another. The functional consequences of the presence of this condition on cellular or tissue function are not well understood. The general consensus is that the condition is an adaptive response rather than a toxicological manifestation; however, additional studies to examine this question are needed. Until this issue is resolved, concerns about phospholipidosis will continue to exist at regulatory agencies. Procedures for the screening of...

Drug-induced phospholipidosis: issues and future directions.

Drug-induced phospholipidosis (PLDsis) is an excessive accumulation of polar phospholipids in cells or tissues/organs caused by xenobiotics. Numerous drugs and chemicals are capable of inducing the storage disorder in animals and humans; however, despite their diverse pharmacological activities, each of these drugs shares common physicochemical properties: a hydrophobic aromatic ring structure on the molecule and a hydrophilic side chain with a charged cationic amine group and therefore are in the group of cationic amphiphilic drugs. In affected cells the appearance of membrane-bound inclusions, primarily lysosomal in origin, with a lamellar structure (lamellar bodies) is a definitive morphologic hallmark. Massive accumulations can occur in animal tissues such as the lung with little effect on organ function. The inducing drug also accumulates in association with the excess phospholipid. Although these alterations are generally reversible after cessation of drug treatment, PLDsis is of regulatory concern and an issue for drug safety for pharmaceutical companies. Thus, the assessment of potential target organ dysfunction and the identification of clinical biomarkers are important objectives for new drug development. Recent advances in biotechnology such as metabonomics and toxicogenomics have been providing novel tools to elucidate the mechanisms of PLDsis and to establish biomarkers for screening tests in the preclinical stages and for monitoring in the clinical phases in addition to conventional approaches such as morphology (lamellar bodies) and biochemical methods including assays of specific metabolites and phospholipase inhibition.

Drug-induced Phospholipidosis : Pathological Aspects and Its Prediction

The identification of phospholipidosis (PPL) during preclinical testing in animals is a recognized problem in the pharmaceutical industry. Depending on the intended indication and dosing regimen, PPL can delay or stop development of a compound in the drug discovery process. Therefore, for programs and projects where a PPL finding would have adverse impact on the success of the project, it would be desirable to be able to rapidly identify and screen out those compounds with the potential to induce PPL as early as possible. Currently, electron microscopy is the gold standard method for identifying phospholipidosis, but it is low-throughput and resource-demanding. Therefore, a low-cost, high-throughput screening strategy is required to overcome these limitations and be applicable in the drug discovery cycle. A recent publication by Ploemen et al. (Exp. Toxicol. Pathol. 2004, 55, 347−55) describes a method using the computed physicochemical properties pKa and ClogP as part of a simple calculation to determine...

Evaluation of a published in silico model and construction of a novel Bayesian model for predicting phospholipidosis inducing potential.

The safety evaluation of fluvastatin, an HMG-CoA reductase inhibitor, in beagle dogs and rhesus monkeys.

Numerous amphiphilic cationic drugs cause generalized phospholipidosis in animals; one of these drugs is the Sandoz compound 200-125, a psychotropic agent. During a 6-month toxicity study in Charles River CD rats, a dramatic increase in foamy macrophages was seen in the lungs. A follow-up experiment was done to study the pathologic basis of these changes including a reversibility phase. Generalized phospholipidosis was induced after 4 weeks of 500 mg/kg/day of 200-125 by gavage. Characteristic pulmonary lesions consisted of extensive accumulations of large pale foamy macrophages as well as granular eosinophilic extracellular material. Lipid analyses of lungs showed marked increases in phospholipids (144%) and cholesterol esters (110%) in rats treated with 200-125. Drug metabolism studies employing 14C-labeled 200-125 showed an affinity for the drug to concentrate in the lungs and lymphoreticular system (spleen, lymph nodes) as well as in the adrenals, liver, and kidney. Reversibility of the phospholipidosis was nearly complete 4 weeks after drug withdrawal. The tissue changes were characterized by transmission and scanning electron microscopy. The potential pulmonary toxicity in humans with the amphiphiles is discussed.

https://journals.sagepub.com/doi/pdf/10.1177/019262338501300410

Generalized Phospholipidosis Induced by an Amphiphilic Cationic Psychotropic Drug

A rare spontaneous tumor was detected in the kidney of an 11-mo-old beagle dog. The tumor was a well-circumscribed cortical mass and was composed of a heterogeneous population of connective tissue cell types. While the primary cell type was a spindle cell associated with prominent collagen deposition, other areas contained bands of smooth muscle cells and poorly cellular myxomatous tissue. The presence of smooth muscle cells was confirmed by transmission electron microscopy and immunoperoxidase techniques. Based on the results, the tumor was diagnosed as a benign mixed mesenchymal tumor.

Mixed Mesenchymal Tumor in the Kidney of a Young Beagle Dog

Embryo-fetal developmental and reproductive toxicology of vinyl chloride in rats.

INTRODUCTION It is well known that the vascular complications of diabetes mellitus represent the major cause of morbidity and mortality among diabetics. Early studies using the light microscope associated thickening of retinal capillary, and glomerular basement membranes with diabetic microangiopathy (1,2,3). Since that time, morphological studies using the electron microscope have confirmed thickening of basement membranes of diabetics in the glomerulus and skeletal muscle capillaries as a consistent pathological feature of the lesion (4,5,6-12). In addition, two reports have correlated diabetic retinography with muscle capillary basement membrane thickening (7.13). The production of rnicroangiopathy in the experimentally diabetic animal has proven to be a very lengthy process requiring 7-9 years in Macaca mulatta and 5-7 years in dogs (14,15). After 6-15 months of streptozotocin-induced diabetes in Macaca mulatta, significant basement membrane thickening of muscle capillaries was not found (16). In s p on t an eo us I y d i a bet ic Maca ca n igra, s I i g h t I y t h i c ke n ed capillary basement membranes have been shown to correlate significantly with thedegree and severityof diabetes (17,18). Basement membrane thickening (BMT) of aortic endothelial cells has been reported in rhesus monkeys after 29 to 30 days of a cholesterol, peanut oil diet (19). Because of this report, it was of interest to determine i f similar BMT occurred in the microcirculation (skeletal muscle) of rhesus monkeys fed such a diet (19). The objectives of this study were to assess skeletal muscle capillary basement membranes of rhesus monkeys by using the electron microscope after an eighteen week feeding study of a cholesterol and peanut oil diet. Also, to determine if such a diet can be used for rapid production of an animal model of basement membrane thickening, possibly similar to the BMT associated with diabetic vascular disease. '

https://tpx.sagepub.com/content/6/2/7.full.pdf

Rodney L. Robison

Papers

The safety evaluation of fluvastatin, an HMG-CoA reductase inhibitor, in beagle dogs and rhesus monkeys.

Generalized Phospholipidosis Induced by an Amphiphilic Cationic Psychotropic Drug

Mixed Mesenchymal Tumor in the Kidney of a Young Beagle Dog

Embryo-fetal developmental and reproductive toxicology of vinyl chloride in rats.

Analysis of Ultrastructural Changes in the Basement Membrane of Muscle Capillaries in Rhesus Monkeys Fed a Cholesterol, Peanut Oil Diet