Phospholipids, toxicants that bind

Toxicants that bind to phospholipids in the cell membrane (e.g., gossypol) affect potassium transport. The resultant hy kalemia produces arrhythmias [visible on the electrocardiogram (EKC) as an increased T-wave amplitude and shortening of the S-T segment]. 

Toxicity is most likely in tissues that interact with the drug. For example, gentamicin is polycationic and binds to anionic phospholipids in the cell membranes of renal proximal tubular cells, where it inhibits phospholipases and damages intracellular organelles. 

The mechanism of hepatotoxicity is therefore currently unclear. It has been suggested that lipid peroxidation is responsible rather than covalent binding to protein. Arylation of other low molecular weight nucleophiles such as coenzyme A and pyridine nucleotides also occurs and may be involved in the toxicity. Bromobenzene is known to cause the inhibition or inactivation of enzymes containing SH groups. It also causes increased breakdown of phospholipids and inhibits enzymes involved in phospholipid synthesis. Arylation of sites on... 

Bone Toxicity. In addition to its effect on calcium absorption, excess absorbed strontium adversely affects bone development in several ways, leading to the development of rickets in children and young animals. Strontium binds directly to hydroxyapatite crystals, which may interfere with the normal crystalline structure of bone (Storey 1961). In addition, excess strontium may prevent the normal maturation of chondrocytes in the epiphyseal plates of long bones (Matsumoto 1976). Excess strontium apparently interferes with the mineralization of complexed acidic phospholipids that is thought to help initiate the formation of hydroxyapatite crystals in developing bone (Neufeld and Boskey 1994). As a result, affected bone contains an excess of complexed acidic phospholipid and a significantly lower ash weight. 

One in every 1,000 people in the United States currently receives lithium, as Li2C03, for the treatment and prophylaxis of manic-depressive behavior. Doses of 250 mg to 2 g per day are administered in order to maintain a 0.5 to 2.0 mM concentration window, outside of which the drug is either toxic or ineffective. The detailed molecular mechanism by which Li ion brings about its remarkable chemotherapeutic effects is largely unknown, but there are various theories. One theory proposes that lithium binds to inositol phosphates, inhibiting their breakdown to inositol, and so reducing inositol-containing phospholipids. A consequence of this chain of events would be disruption of the neurotransmis-... 

PEG)-modified phospholipids provides a hydrophilic shell that surrounds the lipophilic core and creates a steric barrier. PEG derivatives were shown to prevent serum protein binding, to reduce phagocytotic cell-mediated recognition, and to result in increased circulation lifetimes (18). Polyglycerolated phospholipids are said to inhere a similar potential of reducing opsonization processes while showing reduced toxicity (19). 

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