Toxic xenobiotic

Our questions broadened to consider how the transport and metabolic capabilities of these aquatic species compare with those of mammalian species. One reason for asking such a question is to assess whether the presence or absence of these capabilities alters the ability of fish to survive in toxic environments. Survival mechanisms fall into two catagories - behavioral and physiologic. An example of a behavioral mechanism could be as simple as a fish avoiding that area of a stream which contains toxic quantitites of phenol. When external perturbations caused by pollutants are small, homeostatic mechanisms such as those of the liver and kidney, allow fish to adapt to the body of water in which they exist. The problem then is related to defining the limits to which homeostatic phenomena can be stressed in aquatic species. An important reason to establish such information in fish is that bodies of water are the "ultimate sink" for a number of pollutants (12). Thus, while a behavioral response such as removing itself from a toxic environment is invariably available to a mammalian species, this type of response is impossible for a fish if a toxic xenobiotic occurs uniformly throughout an entire body of water. 

Such essential limitations may markedly decrease the reliability and predictive capacity of quantitative structure-toxicity relationships (STRs) in haloalkenes and all other classes of toxic xenobiotics, but recognition of limitations does not suppress the need for predictive tools. In fact, any approach, empirical or mechanistic, that is able to uncover qualitative STR trends and to assign a priori labels of potential toxicity is certainly welcome. 

The lowest dose effects of diuron are seen at 0.27 mg kg-1 per day. Almost all of the low-dose expression changes are related to genes involved with xenobiotic metabolism and transport, including cytochrome P450 enzymes and several transferases. These data indicate that the cells are responding appropriately to a potentially toxic xenobiotic. These effects are widespread across the set of chemicals tested in ToxCast, so it is of interest that 2,4-D does not trigger a similar xenobiotic metabolism response. 

There are several examples in the literature of the integration of studies with cDNA-expressed human P450 enzymes and human liver microsomes which have led to improved understanding of human enzyme-mediated activation of protoxins. Some of these examples are discussed below. Most of these reports have taken a multifaceted approach combining studies in human liver microsomes with cDNA-expressed enzymes. The general metabolic properties of these toxic xenobiotics (e.g. multiplicity of enzymes, differences in affinity and capacity, methods to compare to human liver data, etc.) apply to drugs and drug candidates as well. 

Anders, M. W., W. Dekant, and S. Vamvakas, Glutathione-dependent toxicity. Xenobiotics 22 1135-1145, 1992. 

Discuss some examples of means by which past and current exposure to toxic xenobiotics are detected. 

Xenobiotics can be absorbed across the cellular barriers and may be biologically active and possibly toxic to the cell. Metabolism of these molecules by enzymes to hydrophilic metabolites is a prerequisite for their eventual elimination from the body. However, in some cases bioactivation may also occur, and such metabolites may be toxic. Xenobiotic metabolism has therefore been widely studied since the early 1800s [1]. The parent molecule and the products of metabolic pathways may also be involved in drug interactions where they... 

The activity of quinone reductase, a major protective enzyme, was increased 2-3-fold in first trimester human placental extracts in vitro when incubated for 6 hours with benz[a]anthracene. dibenz[a,h]anthracene, and chrysene at a concentration of 50 jmol (Avigdor et al. 1992). Based on these results, it can be postulated that the early placenta is capable of metabolizing certain toxic xenobiotics such as PAH quinone metabolites to inactive intermediates thereby protecting the developing embryo. 

Though large numbers of pesticides and other toxic xenobiotics have been shown to be substrates for GSTs, relatively few drugs are biotransformed by GST. Among them are ethacrynic acid, doxorubicin, thiotepa. 

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