Toxicity, mediated

Heald S, RO Jenkins (1994) Trichloroethylene removal and oxidation toxicity mediated by toluene dioxygenase of Pseudomonas putida. Appl Environ Microbiol 60 4634-4637. 

The use of the reticulo-endothelial system (RES) was the first approach to liver contrast agents. As an adjunct, spleen imaging would also be possible with a contrast agent that is taken up by the RES. The Kupffer cells of the liver, which represent 10% of all hepatic cells, constitute the major portion (80-90%) of all fixed macrophages and they are extremely effective in the phagocytosis of all types of particles. The downside of the use of this mechanism, however, is the concomitant release of toxic mediators that might and - as a matter of fact - often has made this approach non-feasible. Adverse events provoked by the mediators are changes in blood pressure (most often hypotension) and fever. 

Thus, exposure to any of these enzyme inducers concurrent with or after exposure to diazinon may result in accelerated bioactivation to the more potent anticholinesterase diazoxon. The extent of toxicity mediated by this phenomenon is dependent on how fast diazoxon is hydrolyzed to less toxic metabolites, a process that is also accelerated by the enzyme induction. Similarly, concurrent exposure to diazinon and MFO enzyme-inhibiting substances (e.g., carbon monoxide ethylisocyanide SKF 525A, halogenated alkanes, such as CC14 alkenes, such as vinyl chloride and allelic and acetylenic derivatives) may increase the toxicity of diazinon by decreasing the rate of the hydrolytic dealkylation and hydrolysis of both parent diazinon and activated diazinon (diazoxon) (Williams and Burson 1985). The balance between activation and detoxification determines the biological significance of these chemical interactions with diazinon. 

Furthermore, there are many unanswered questions regarding idiosyncratic drug toxicity mediated by immune mechanisms, and the above explanations are not always sufficient. Some cases do not fit into the classical hapten hypothesis model. For example, antidrug antibodies are not always detectable. Immune reactions can take a period of months or even years to develop (e.g., hydralazine see below). 

A large body of evidence in the literature supports the idea that antibodies directed against HER-2 can inhibit the growth of HER-2-expressing tumors through several mechanisms, including antibody-dependent, cell toxicity-mediated inhibition of HER-2 signal transduction. 

More in-depth behavioral tests are required if dose-related toxicant effects are noted in screening tests. These tests may also be required as part of more selective toxicological screening, such as for developmental neurotoxicity. Focused tests of neuromotor function and activity, sensory functions, memory, attention, and motivation help to identify sites of toxicant-mediated lesioning, aid in the classification of neurotoxicants, and may suggest mechanisms of action. Some of these tests, like the schedule-controlled operant behavior tests for cognitive function, require animal training and extensive operator interaction with the animals. 

Further information regarding endocrine effects of DEHP can be found in the following Sections 3.2.2.5 Reproductive Effects, 3.2.2.6 Developmental Effects, 3.5.2 Mechanisms of Toxicity, and 3.6 Toxicities Mediated Through the Neuroendocrine Axis. 

Another central element of the Grishko hypothesis is the upregulation of inducible nitric oxide synthase (iNOS). Since the induction of iNOS is often associated with extensive nitric oxide formation, it is commonly a toxic event. However, nitric oxide formation is not detrimental in all cell types. Dimmeler et al. (1997) found that nitric oxide protects human endothelial cells against angiotensin II-mediated apoptosis. A key variable appears to be the amount of nitric oxide produced. In the cardiomyocyte, sufficient levels of nitric oxide are generated to cause the formation of toxic levels of peroxynitrite, while in endothelial cells, ROS, rather than reactive nitrogen species, appear to be the toxic mediators of apoptosis. 

The study of plant population toxicology is mandatory if we are to understand and eventually to ameliorate the problem of toxicant-mediated changes to the world around us. Rather than just being an interesting phenomenon to be studied by a few plant pathologists, the fact that toxic air can threaten our food supply stimulates us to greater concern. We still depend upon plants to exist. Phytotoxic response among many individual plants and plant populations is a fact, and adverse effects on food production are a matter of record. The papers in this volume address themselves to the problem. 

Ponce P, Cruz J, Travassos J, Moreira P, Oliveira J, Melo-Gomes E, Gouveia J. Renal toxicity mediated by continuous infusion of recombinant interleukin-2. Nephron, 1993,64[1] 114-118. 

De-risking developmental toxicity-mediated drug attrition in the pharmaceutical industry... 

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