Cell Death chemically induced

The other factor that may determine the type of cell death is the chemical structure of inducing agents [14]. We have recently found that u,(>-unsaluraled ketones such as 4,4-dimethyl-2-cyclopenten-l-one, a-methy-lene-y-butyrolactone, 5,6-dihydro-2H-pyran-2-one [15], codeinone [16], and morphinone [17] and a-hydroxylketones such as 3,3,3-trifluoro-2-hydroxy-1-phenyl-1-propanone induced caspase-independent cell death [18], induced vacuolization or autophagosome formation engulfing organelles, but without induction of apoptosis markers. 

The main types of cellular injury induced by chemical compounds are necrotic and apoptotic (programmed) cell death. Necrosis implies chaotic ending... 

Cytotoxicity. The liver is the primary target organ for a variety of drugs and chemicals (Hasemen et ah, 1984 Farland et ah, 1985). The prevalence of drug-and chemical-induced liver injury is of concern because some xenobiotics can produce liver damage at dose levels that are magnitudes below that which causes cell death (Plaa, 1976). Environmental and commercial chemicals can increase this effect by as much as 100-fold (Plaa and Hewitt, 1982 Plaa, 1976). Studies of early cell injury caused by exposure to a toxicant can be undertaken easily in monolayer cultures of hepatocytes, whereas early cell injury is very difficult to assess in vivo. 

Based on the kno vledge of the processes of T cell sensitization by chemicals and the importance of T cells in induction of autoimmune diseases a number of key indicators of autoimmunogenic compounds can be defined. These include the possibility to be subject of metabolic conversion (either intra- or extra-hepatically), the capacity to activate dendritic cells, to induce cytokine production (in any cell type), or the potency to cause cell stress or cell death. Most of these processes can be studied in vitro, but none of the available methods have been tested for this purpose and often chemicals may behave completely different in vitro than in vivo. However, much can be learned from initiatives to design alternative methods for contact allergens, as many of these basic processes that lead to T cell sensitization are similar for allergenic and autoimmunogenic chemicals. 

It seems that toxic chemicals will induce apoptosis after low doses or early after high doses but necrosis later after high doses. Both forms of cell death involve similar cellular and metabolic changes. The MPT seems to be crucial, as agents that block this process will actually prevent both apoptosis and necrosis (cyclosporin A, Bcl-2 overexpression). 

Some chemical-mediated cell death involves this system also. For example, the spermatocyte death caused by mono-(2-ethylhexyl)phthalate or 2,5-hexanedione (toxic metabolite of hexane) is due to apoptosis. This is induced in the spermatocytes by Fas ligand expressed on the surface of the Sertoli cells in which the microtubules have been damaged by the chemicals. As Sertoli cells are essential for support of the spermatocytes, damaged Sertoli cells are a "liability."... 

Nicotera P., Bellomo G., and Orrenius S. 1992 Calcium-mediated mechanisms in chemically induced cell death. Annu Rev Pharmacol Toxicol 32, 449 170. 

Many chemicals cause a decrease in brain size during fetal development. Changes in brain size can be caused in various ways. A decreased brain weight may be a consequence of general undernutrition caused by effects on placental functioning. Examples of other possible mechanisms are inhibition of cell multiplication or cell growth, increased cell death, disrupted trophic effects induced by changes in cell maturation and neurochemistry. 

Cells can be killed by external agents or can be induced to commit suicide via a pattern of events called programmed cell death or apoptosis. Injuries from external agents include mechanical damage and exposure to toxic chemicals (e.g. chemotherapy). Substances toxic to cells are called... 

Time course experiments can be performed using different classes of control toxins to determine the length of exposure necessary to induce apoptosis or result in necrotic cell death. A toxin with properties that disrupt cell membranes will result in rapid necrotic cell death. Other chemicals may not become toxic until after conversion by modifying enzymes in the cytoplasm. In many cases, subpopulations of cells at different stages of the cell cycle may undergo cell death at different times. 

The final type of chemical toxicity that will be presented are the vesicants, chemicals that cause blisters on the skin. There are two classes of blisters that implicate different mechanisms of vesication. Intraepidermal blisters are usually formed due to the loss of intercellular attachment caused by cytotoxicity or cell death. The second class occurs within the epidermal-dermal junction (EDJ) due to chemical-induced defects in the basement membrane components. The classic chemical associated with EDJ blisters is the chemical warfare agent sulfur mustard (bis-2-chloroethyl sulfide HD). HD is a bifunctional alkylating agent that is highly reactive with many biological macromolecules, especially those containing nucleophilic groups such as DNA and proteins. 

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