Phospholipids storage

Phospholipidosis, a phospholipid storage disorder, is characterized by an excessive accumulation of intracellular phospholipids. Compounds that induce phospholipidosis include a wide variety of pharmacological agents (antipsy-chotics, antidepressants, antiarrhythmics, and cholesterol-lowering agents). These compounds are of concern for the pharmaceutical industry because a candidate pharmaceutical agent can be rejected because of evidence of inducing phospholipidosis in a preclinical animal study. Phospholipidosis is widely reported in rats and is identified by the accumulation of phospholipids in the lysosomes of many cell types. 

Kodavanti UP, Mehendale HM (1990) Cationic amphiphilic drugs and phospholipid storage disorder. Pharmacol Rev 42 327-354... 

In 1963, SwEELEY and Klionsky succeeded in chemical identification of the stored material in ACD. They isolated from the kidney of a patient (Klionsky et al. 1966) large amounts of a glycolipid incorporating three hexose units and another component with two hexose units and sulfur and thus established that ACD was not a phospholipid storage disease. 

Properties Fine powd., superior odor and flavor profile 97% min. phospholipid Storage Hygroscopic store in sealed containers below 25 C protect from light and moisture... 

Peroxidation of lipids is another factor which must be considered in the safety evaluation of liposome administration. Smith and coworkers (1983) demonstrated that lipid peroxides can play an important role in liver toxicity. Allen et al. (1984) showed that liposomes protected by an antioxidant caused less MPS impairment than liposomes subjected to mild oxidizing conditions. From the study of Kunimoto et al. (1981) it can be concluded that the level of peroxidation in freshly prepared liposome preparations and those on storage strongly depends both on the phospholipid fatty acid composition and on the head group of the phospholipid. Addition of appropriate antioxidants to liposomes composed of lipids which are liable to peroxidation and designed for use in human studies is therefore necessary. 

Fat absorbed from the diet and lipids synthesized by the liver and adipose tissue must be transported between the various tissues and organs for utilization and storage. Since lipids are insoluble in water, the problem of how to transport them in the aqueous blood plasma is solved by associating nonpolar lipids (triacylglycerol and cholesteryl esters) with amphipathic hpids (phospholipids and cholesterol) and proteins to make water-miscible hpoproteins. 

STORAGE OF LIPID MESSENGERS IN NEURAL MEMBRANE PHOSPHOLIPIDS 576... 

Phospholipid concentration was determined using our modification of Bartlett s procedure (49,53). Cholesterol concentration and purity were determined by HPLC or enzymatically by cholesterol oxidase (49,53). Purity of phospholipids as raw materials, and the extent of their hydrolysis during various steps of liposome preparation and liposome storage, were assessed by TLC and enzymatic determination of the increase in level of nonesterified fatty acids (10,38,49-51,53). 

In addition to fuel storage, fats and fatty acids are now known to have several key roles in the body, e.g. as messengers, precursors of molecular messengers, gene regulators, components of phospholipids (which form the major part of membranes) and possible modifiers of the immune response. 

General physiological roles for fatty acids in cellular lipids are caloric storage, membrane fluidity, and prostaglandin precursors. The first of these mainly involved the formation and hydrolysis of triacyl glycerols, transport and activation of non-esterified fatty acids, and other steps leading to energy conversion (110). The second role primarily involves activation and incorporation into 1- and 2- positions of different phospholipids which form a major part of membranes. The third role is linked to the requirement for certain unsaturated fatty acids in the diets of most animals (110). 

Diethanolamine has been shown to inhibit choline uptake into cultured Syrian hamster embryo (SHE) and Chinese hamster ovary cells and to inhibit the synthesis of phosphatidylcholine in in-vitro systems in a concentration-dependent, competitive and reversible manner (Lehman-McKeeman Gamsky, 1999, 2000). Diethanolamine treatment caused a marked reduction in hepatic choline metabolite concentrations in mice following two weeks of dermal dosing. The most pronounced reduction was in the hepatic concentration of phosphocholine, the intracellular storage form of choline (Stott et al, 2000). Moreover, the pattern by which choline metabolites were altered was similar to the pattern of change that has been observed following dietary choline deprivation in rodents (Pomfret et al, 1990). Excess choline also prevented diethanolamine-induced inhibition of phosphatidylcholine synthesis and incorporation of diethanolamine into SHE cell phospholipids (Lehman-McKeeman Gamsky, 2000). 

As might be anticipated, on their own these materials undergo complex decomposition reactions, illustrated in the case of phospholipids used to stabilize injectable lipid emulsions. As discussed later, these systems are usually steam-sterilized so that they readily hydrolyze both in the presence of heat during the sterilization process and on subsequent storage (Figure 9.4). Oxidation reactions also occur in the presence... 

Hydrolysis that occurs to some degree on autoclaving and storage results in the production of corresponding lyso-compounds, phospholipids without one of the acyl chains. These materials are called lyso- because, on their own, lyso-compounds produce lysis of red blood cells and are generally regarded as toxic. Analytically it is not difficult to demonstrate that there are significant quantities of these compounds present in injectable emulsions but there have never been any clinical reports of toxicity. The probability is that these materials form some type of association complex with the other phospholipids present and are not available on their own to exert any effect which would result in toxicity. 

---