Lipids water transport, cellular

Conjugation of lipophilic xenobiotics to polar cellular constituents renders the xenobiotic more water-soluble. While the lipophilic parent xenobiotics could readily diffuse into the cells, the increase in polarity associated with conjugation greatly reduces the ability of the compound to diffuse across the lipid bilayer of the cell membrane thus trapping the compound within the cell. The polar conjugates must therefore rely upon active transport processes to facilitate efflux from the cell. Hepatocytes, as well as other cells involved in chemical detoxification, are rich with members of the ATP-binding cassette superfamily of active transport proteins (ABC transporters). Cellular efflux of xenobiotics by these transporters is often referred to as Phase III elimination because Phase I or II detoxification processes often precede and are a requirement of Phase III elimination. A detailed description and discussion of elimination and transporters is presented in Chapter 15. 

After synthesis on the smooth ER, the polar lipids, including the glycerophospholipids, sphingolipids, and glycolipids, are inserted into specific cellular membranes in specific proportions, by mechanisms not yet understood. Membrane lipids are insoluble in water, so they cannot simply diffuse from their point of synthesis (the ER) to their point of insertion. Instead, they are delivered in membrane vesicles that bud from the Golgi complex then move to and fuse with the target membrane (see Fig. 11-23). Cytosolic proteins also bind phospholipids and sterols and transport them between cellular membranes. These mechanisms contribute to the establishment of the characteristic lipid compositions of organelle membranes (see Fig. 11-2). 

Cholesterol is an essential component of cellular membranes. In addition to dietary sources, we can also synthesize cholesterol. Cholesterol is transported in the blood as a lipoprotein, which is an aggregate of water-soluble proteins, cholesterol, and other lipids, including triglycerides. Proteins are denser than lipids,... 

The mechanism in hepatic cellular metabolism involves an electron transport system that functions for many drugs and chemical substances. These reactions include O-demethylation, N-demethyla-tion, hydroxylation, nitro reduction and other classical biotransformations. The electron transport system contains the heme protein, cytochrome P-450 that is reduced by NADPH via a flavoprotein, cytochrome P-450 reductase. For oxidative metabolic reactions, cytochrome P-450, in its reduced state (Fe 2), incorporates one atom of oxygen into the drug substrate and another into water. Many metabolic reductive reactions also utilize this system. In addition, there is a lipid component, phosphatidylcholine, which is associated with the electron transport and is an obligatory requirement for... 

Transient water pores in cellular membranes are involved in several relevant processes, such as maintenance of osmotic balance, drug and antibody delivery into cells, and ion transport across the membrane. Understanding ion transport across membranes is especially important, because membranes strive to maintain a cationic electrochemical gradient used for ATP synthesis. Yet, ions leak through lipid membranes, and understanding the mechanisms associated with ion leakage would allow one to control membrane properties better in related applications. 

The common function of all apolipoproteins is to help solubilize neutral lipids in the circulation. The apolipoproteins bind readily to PL-water interfaces and, under appropriate conditions, can spontaneously form discrete particles with PL. In vivo, the assembly of apolipoproteins with lipids to form lipoproteins may require the assistance of cellular proteins such as the microsomal lipid transfer protein or the ABCAl transporter. 

In the previous section, the permeation of solutes through uniform lipid membranes was discussed however, cell membranes and cellular barriers are not perfectly uniform (Figure 5.1). Proteins interrupt the continuous lipid membrane and provide an additional pathway for the diffusion of water-soluble molecules. Protein channels in the membrane, for example, permit the selective diffusion of certain ions. In the blood vessel wall, water-filled spaces between the adjacent endothelial cells provide an alternate path for transport. 

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