Cytotoxicity, chemically induced

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. 

Cytotoxicity may decrease cell surface expression and transcription of markers. Thus, if concentration of test chemical induces low cell viability then measurement of cell surface expression and transcription is limited. In addition, donor variability may introduce differences in fluorochrome-conjugated monoclonal antibody expression (Aiba et al. 1997). 

The precise biochemical mechanisms leading to irreversible cell injury and nephrotoxicity are not well-defined. Many diverse biochemical activities occur within the kidney, and interference with one or more of these functions may lead to irreversible cell injury. Rather than any one single mechanism mediating chemically induced nephrotoxicity, it is likely that a toxicant alters a number of critical intracellular functions, ultimately leading to cytotoxicity and cellular necrosis. 

If a cytotoxic chemical is capable of being absorbed across the stratum corneum barrier, it has the potential to cause toxicity to the skin. Chemical-induced damage... 

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. 

Pharmacologically, vanillin can accelerate bile secretion. Vanillin is capable of effectively minimizing methotrexate-induced chromosomal damage. Vanillin is an anticlastogenic agent it has also been demonstrated to inhibit gene mutations in both bacterial and mammalian cells. Vanillin enhances or suppresses chemical-induced cytotoxicity, mutations, and chromosome aberrations. 

Phototoxicity or chemical phototoxicity is the term used for an acute reaction that can be induced by a single treatment with a chemical and UV or visible radiation. The basic mechanism of phototoxicity can be described as an increase in toxicity of a chemical induced by exposure to UV or visible radiation. Therefore the phototoxic potential of a chemical can be measured as an increase in cytotoxicity after exposure to UV or visible light. The 3T3 NRU PT test is a validated and robust in vitro phototoxicity test according to the criteria laid down by the ECVAM Workshop on practical aspects of the validation of toxicity test procedures and the conclusion of the ECVAM/COLIPA validation study [72], Owing to the convincing performance of the 3T3 NRU PT test, the test is now established and in use in industry laboratories to screen... 

If a cytotoxic chemical is capable of traversing the stratum corneum, it may cause toxicity to the skin as a function of its inherent potential to modify cellular function. Complex quantitative structure activity relationship (QSAR) models developed to assess general cytotoxicity may be applicable to define this inherent toxic potential. The clearest approach to assessing chemical-induced damage to skin is to assess what abnormalities occur when the specific anatomical structures discussed above are perturbed after exposure to topical compounds, since this will be the response modeled in a computational toxicology exercise. 

Liriodenine was found to be active in the brine shrimp lethality test (LC50 2.03 pg/ml) but was inactive in the 9PS (a chemically-induced murine lymphocytic leukemia) and 9KB (human nasopharyngeal carcinoma) cytotoxicity tests [296],... 

The CTZ, located in the area postrema of the fourth ventricle of the brain, is a major chemosensory organ for emesis and is usually associated with chemically induced vomiting. Because of its location, blood-borne and cerebrospinal fluid toxins have easy access to the CTZ. Therefore cytotoxic agents stimnlate primarily this area rather than the cerebral cortex and visceral afferents. Similarly, pregnancy-associated vomiting probably occurs through stimulation of the CTZ. 

While only a simulation, this model still serves to illustrate 1) the potential impact of cytotoxicity upon the dynamics of DNA turnover and the background rate of spontaneous mutation/proto-oncogene activation or, in the case of genotoxins, the rate of chemically-induced mutation and 2) the potentially large differences in potency, at a macromolecular level, which may exist between these two classes of carcinogens. One factor which this model does not take into account, however, is the potential Impact of purely receptor-mediated promotional activity of a cytotoxic compound. 

The activation of protein kinase C and subsequent induction of cell proliferation by cytotoxic chemicals has been suggested by Roghani et al. (64). The inappropriate activation of this enzyme by a chemical-receptor complex is believed to play a role in the promotion process. The activation of protein kinase C may subsequently result in the activation of a number of cytoplasmic proteins through inductional phosphorylation and set off a chain of events which includes enhanced cell proliferation in the absence of regenerative cell replication. The distinction between cytotoxicity and promotion may not always be clear. As recently discussed by Trump and Berezesky (65), chemically-induced alterations in the cellular dynamics of calcium regulation may result in a wide range of changes, many of which are similar to those caused by protein kinase C... 

Chloroform. As an example of the cytotoxic threshold, let us consider chloroform. This chemical induces liver and kidney tumors in rodents upon prolonged administration of high doses (10). However, chloroform does not induce mutations in bacterial test systems (11, 12), nor does it induce significant alteration of DNA isolated from organs of animals exposed vivo to chloroform (13). However, chloroform does induce extensive tissue damage with subsequent cellular regeneration at the same sites where tumors later develop (Table 3). When the exposure to chloroform is reduced to levels which do not produce clinically observable tissue damage, tumors fail to develop upon chronic exposure (13,... 

Lash, L.H., Putt, D.A., and Benipal, B. (2014b) Multigenerational study of chemically induced cytotoxicity and proliferation in cultures of human proximal tubular cells. Int. J. Mol. Sci. 15, 21348-21365. 

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