Cell metabolism disruption

The antimetabolites interfere with various metabolic functions of cells, thereby disrupting normal cell functions. They inactivate enzymes or alter the structure of DNA, changing the DNA s ability to replicate These drag are most effective in the treatment of rapidly dividing neoplastic cells. Examples of the antimetabolites include methotrexate and fluorouracil (Adrucil). 

Hypothermia—Indirect cryodestruction Metabolic uncoupling Energy deprivation Ionic imbalance Disruption of acid-base balance Waste accumulation Membrane phase transitions Cytoskeletal disassembly Frozen State—Direct cryodestruction Water solidification Hyperosmolality Cell-volume disruption Protein denaturation Tissue shearing Intracellular-ice propagation Membrane disruption Microvascular Thawed State Direct effects... 

HI. Disruption of cell metabolism with inhibition of proliferation. At dosages below those needed to treat malignancies, some cytostatics are also employed for immunosuppression, e.g., azathioprine, methotrexate, and cyclophosphamide (p. 298). The antiproliferative effect is not specific for lymphocytes and involves both T- and B-cells. 

Antibiotics can be classified according to their effects on the biochemistry or molecular biology of pathogens. There are ribosomal inhibitors (macrolides), cell wall disrupters 0-lactams), DNA disturbers (fluoroquinolones), and metabolic poisons (trimethoprim-sulfamethoxazole). Antibiotics also can be classified according to whether they are static (inhibitory) or cidal (lethal). The classification of drugs as either static or cidal is based on laboratory assessment of the interaction of pathogen and antibiotic drug. 

These compounds vary, from the natural product rotenone (from Derris or Lonchocarpus root, used to control vegetable and fruit insects) to the synthetics sulfluramid and hydramethylnon (used to control mites and cockroaches). Interestingly, the highest acute toxicity to mammals is caused by the natural product rotenone. These compounds affect the production of adenosine triphosphate (ATP), the energy storage molecule of the cell that is produced by mitochondria, the powerhouse of the cell. The disruption of energy metabolism and the subsequent loss of ATP result in a slowly developing toxicity, and the effects of all these compounds include inactivity, paralysis, and death. 

OEHHA Office of Environmental Health Hazard Assessment OSHA Occnpational Safety and Health Administration Osteogenic sarcoma Cancer associated with bone structures Oxidation Chemical addition of oxygen to break down pollutants or organic waste, for example, destruction of chemical substances such as cyanides, phenols, and organic sulfur compounds in sewage by bacterial and chemical means Oxidative stress Process whereby the metabolic balance of a cell is disrupted by exposure to environmental substances, resulting in accumulation of free radicals, which can damage the cell... 

Disrupted calcium homoeostasis Normal concentrations of ionized calcium in the cytosol (0.05-0.2 pM), in the overall liver cell (0.5-2.0 pM) and in the extracellular space (1.0 pM) maintain the function of numerous Ca-dependent enzymes and structural elements of the liver cell. Calcium homoeostasis is maintained by the regulatory functioning of all Ca transportation systems, energy supply in the form of ATP and intactness of the biomembranes. Defective calcium homoeostasis can cause an increase in calcium in the cytosol, which in turn activates calcium-dependent enzymes, alters the metabolic functions of the cell and disrupts the gap junctions and tight junctions. These biochemical changes result in various forms of hepatocellular degeneration and ultimately in cell death, (s. fig. 21.12)... 

The Sertoli cell plays a key metabolic role in the processes of germ cell development. Compounds that disrupt Sertoli cell metabolism would be expected to cause testicular toxicity. For example, 1,3-dinitro-benzene and other nitroaromatic compounds cause testicular toxicity apparently by disruption of Sertoli cell function. These compounds can undergo reductive metabolism to toxic nitroso intermediates, which may be ultimately responsible for the Sertoli cell toxicity. As indicated above, microtubules play an important role in support and transport processes. Hexanedione has been studied extensively as an agent capable of altering testicular microtubules. Other compounds that disrupt microtubule assembly and Sertoli cell function include the fungicide ben-omyl and the antiinflammatory agent colchicine, both of which prevent the assembly of testicular tubulin into microtubules. 

It is now established that once inside the cell, an organic acid will encounter a higher pH, dissociate to produce protons and anions, and also acidify the cytoplasm (Papadimitriou et al., 2007). The anionic part of the organic acids that cannot exit the microbial cell in its dissociated form will, therefore, accumulate within the cell and disrupt many metabolic functions. This will also lead to an osmotic pressure increase, which the organism will not be able to handle (Gauthier, 2005). 

Evidence accumulated over an involvement of indirect causes to cancer due to epigenetic alterations such as hyper- or hypo-methylation and CpG-island promoter region silencing, together with not strictly DNA-related effects (e.g., altered oxygen metabolism, oxidative stress, cell membrane disruption, or even mitochondrial membrane permeability transition induction) [22,28,29],... 

Schirmer, K., A.G.J. Chan and N.C. Bols. Transitory metabolic disruption and cytotoxicity elicited by benzo[a jpyrene in two cell lines from rainbow trout liver. J. Biochem. Mol. Toxicol. 14 262-276, 2000. 

Figure 16.2. Mechanisms of cellular toxicity. Tissues are comprised of cells, and each cell is defined by its cell membrane. The cell membrane is composed of a lipid bilayer, which contains proteins that function as ion channels and receptors. Compounds that disrupt the membrane environment can directly or indirectly alter the normal function of these proteins. In each cell, there are numerous subcellular organelles, all of which are potential targets for toxicity. Cytochrome P450 enzymes in the endoplasmic reticulum may metabolize drugs that enter the cell. Metabolism has one of two effects on the drug s potential toxicity (l)it may reduce toxicity by eliminatingparent compound, or (2) it may increase toxicity by generating a reactive (electrophilic) metabolite. Drugs may inhibit critical functions in mitochondria or damage DNA in the nucleus, which can lead to cell death by apoptosis or necrosis.

Frataxin (Figure 2) has recently been identified as a likely physiological iron donor to ISU during assembly of the [2Fe-2S] cluster core 10, 21-23), and to ferrochelatase for the final step of heme biosynthesis 24, 25), Dysfunction of fi-ataxin results in mitochondrial iron accumulation and oxidative damage to mitochondrial DNA 26, 27), as well as the potential to disrupt other cellular processes dependent on such iron cofactors. This is the first characterized example of an iron-delivery protein and it remains to be seen how relevant its functional chemistry will be, relative to cell metabolism across a spectrum of organisms. As noted later, the absence of sequence homologs in certain other organisms does not preclude the presence of structural and functional... 

Haloprogin is an iodinated acetylene active against dermatophytes (54). Haloprogin is only used for topical applications (Table 40.1). The mechanism of haloprogin is not clear, but it appears to lead to nonspecific metabolic disruption. It has been demonstrated to interfere Afith DNA biosynthesis and cell respiration. 

Metabolic disruptions may result in inhibition of cell enlargement. Key (9) found that actinomycin D, an inhibitor of DNA directed RNA synthesis (10), and puromycin, an inhibitor of protein synthesis, will prevent cell enlargement in soybean Glycine max L. Merr.) hypocotyls. Key concluded RNA and protein synthesis are essential for the process of cell elongation to proceed at a normal rate. The following year, Cleland reported the inhibition of cell enlargement caused by actinomycin D was not caused by an inhibition of auxin-induced cell wall loosening... 

Some plants, such as spinach and tobacco, will absorb even larger amounts of potassium than of nitrogen when the avadable supply is large. The exact role of potassium has not been determined with certainty but the evidence indicates that it functions in a variety of ways (Evans and Sorger, 1966). Hewitt (1951) expressed the opinion that it helps to maintain cell organization, hydration and permeability and hence directly or indirectly influences many enzyme systems. It may also help to maintain available supplies of iron, which is so essential in chlorophyll formation and functioning. Where potassium is deflcient it has often been noted that carbohydrates tend to accumulate in plants, presumably because of a disruption of the synthetic metabolism, but a causal relationship has not been established. In cell metabolism there are such close interrelations between potassium, calcium and magnesium that it is difficult to establish the individual roles of each of these elements. 

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