Interference with Cell Membrane Structure

Cell membranes are bilayers of amphipathic acids, for example phospholipids and sterols, which contain globular proteins. The structure is governed by the essential requirement for stability in an aqueous environment, that is, the hydrophobic tails of the lipid molecules point towards each other, leaving the outer surfaces composed of polar, hydrophilic groups. 

The guanidines, comprising dodine and guazatine, have long-chain alkyl groups and act as non-specific detergents. The lipophilic alkyl chain attaches to the lipid fraction of membranes whilst the polar guanidino portion remains in the aqueous phase. The result is a disruption in the membrane permeability characteristics and active transport systems. 

Guazatine is a mixture of guazatine acetates, recommended as a broad spectrum cereal seed treatment, a foliar spray or a dip treatment for fruit and seed potatoes. 

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Trichothecene mycotoxin Toxin produced by fungal molds it inhibits protein synthesis, impairs DNA synthesis, and interferes with cell membrane structure and function. 

Trichothecene mycotoxins are produced by a number of fungal molds of the Fusarium, Myrotecium, Trichoderma, and Stachybotrys genera. They inhibit protein synthesis, impair DNA synthesis, and interfere with cell membrane structures and functions. The potential routes of exposure are inhalation, ingestion, and skin absorption. A terrorist may take advantage of any of these routes. 

In addition to effects on biochemical reactions, the inhibitors may influence the permeability of the various cellular membranes and through physical and chemical effects may alter the structure of other subcellular structures such as proteins, nucleic acid, and spindle fibers. Unfortunately, few definite examples can be listed. The action of colchicine and podophyllin in interfering with cell division is well known. The effect of various lactones (coumarin, parasorbic acid, and protoanemonin) on mitotic activity was discussed above. Disturbances to cytoplasmic and vacuolar structure, and the morphology of mitochondria imposed by protoanemonin, were also mentioned. Interference with protein configuration and loss of biological activity was attributed to incorporation of azetidine-2-carboxylic acid into mung bean protein in place of proline. 

The mercuric ion, Hg2 +, which is obtained after oxidation in the red blood cells and other tissues, is able to form many stable complexes with biologically important molecules or moieties such as sulphydryl groups. The affinity of mercury for sulphydryl groups is a major factor in the understanding of the biochemical properties of mercuric compounds, resulting in interference with membrane structure and function and with enzyme activity. 

This chapter is divided into three sections. The first section covers renal tubule transport mechanisms. The nephron is divided structurally and functionally into several segments (Figure 15-1, Table 15-1). Many diuretics exert their effects on specific membrane transport proteins in renal tubular epithelial cells. Other diuretics exert osmotic effects that prevent water reabsorption (mannitol), inhibit enzymes (acetazolamide), or interfere with hormone receptors in renal epithelial cells (aldosterone receptor blockers). The physiology of each segment is closely linked to the basic pharmacology of the drugs acting there, which is discussed in the second section. Finally, the clinical applications of diuretics are discussed in the third section. 

Phase I and II clinical trials indicated that acronycine reduced pain of the spine in some patients with multiple myeloma [280,282,283]. Acronycine has been reported to cause leukopoenia and to have CNS-depressant activity [284], Biochemically, acronycine inhibits incorporation of extracellular nucleosides into the RNA and DNA of leukaemia L-5178Y cell culture. There is, however, no evidence of interaction between acronycine and DNA or inhibition of template activity of DNA. This alkaloid does not inhibit nucleic acid synthesis in the cell, but rather inhibits the accumulation of extracellular uridine or thymidine, as nucleotides, in the intracellular precursor pool [285, 286], Acronycine, acting primarily on membranous organelles [287], seems to interfere with the structure, function and/or turnover of cell membrane components, thereby changing the fluidity of the plasma membrane [288]. 

Ever since the discovery, by Ledbetter and Porter,88 of microtubules below the surface of the plasma membrane, suggestions have been made that these structures play some role in microfibril orientation. The suggestion arose because of two observations that (I) the orientation of microtubules has very frequently, but not always, been observed to be parallel to the orientation of the microfibrils most recently synthesized, and (2) agents, such as colchicine, that disrupt microtubules interfere with the orientation, but not the synthesis, of cellulose microfibrils. The literature pertaining to these studies has been well reviewed by Robinson,4 Schnepf and coworkers,89 Hepler and Palevitz,90 and Heath.91 In sum, the present evidence seems to favor some role for microtubules in orientation in some cases, such as the studies on guard cells by Palevitz and Hepler,92 and a series of papers on Oocystis by Robinson and coworkers,84,93-95 the case for micro-... 

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