Molecular toxicity mechanisms

Typically, ADME studies are included in the battery of tests used to characterize the toxicity of chemicals, as well as other studies designed to trace the underlying molecular and cellular events that lead to toxicity. These studies of toxic mechanisms take many forms, and are better viewed as research studies no general characterization of them will be made here, but some of the things such studies can reveal to aid understanding of risk will be mentioned at appropriate places in the remaining sections of the book. 

A plethora of other effects on cell constituents from proteins to lipids to DNA is also documented in the early literature without, however, establishing any link between these reactions and the toxic consequences. Such an inability to deduce a toxic mechanism is not necessarily surprising. After all, aminoglycosides are highly aggressive drugs that kill cells and tissues, and a cell in the process of destruction will show a multitude of deranged biochemical and molecular pathways. 

Ivanciuc, O. (2002) Support vector machine idetification of the aquatic toxicity mechanism of organic compunds. Internet Electronic Journal of Molecular Design and BioChem Press 1, 157-1721 http //www.biochempress.com/av01 0157.html and ftp //biochempress.com/ieimd 2002 1 0157.pdf). 

However, the most important driving force for performing in vitro toxicity studies is a scientific one if one wishes to study the toxicity mechanisms of action of a compound, it is no longer appropriate to rely on the apical endpoints for toxicity that are the commonly measured parameters in an animal study. A focus on these mechanisms, in relation to the events following the molecular initiating event, eventually leading to an adverse outcome gives... 

The toxic mechanisms of photosensitization have been reviewed recently (1-3) and will not be dealt with here. The reader is referred to these references for detailed discussions of the cellular targets and molecular mechanisms of phototoxicity mediated by various natural products. 

Many microorganisms and plants are capable of transforming toxic chemical species into less toxic forms (e.g., Lytle et al. 1996, 1998 Hunter et al. 1997). Some plants are particularly useful for remediation of contaminants in soils and natural waters because they hyperaccumulate specific toxins (e.g., Van der Lelie et al. 2001 Fuhrmann et al. 2002). In most cases, however, the molecular-scale mechanisms of these transformations or of hyperaccumulation are not known. This is a fertile research field for geochemists and mineralogists that will require multidisciplinary studies and will benefit from SR-based microspectroscopy methods. 

QSAR models can be a valuable means of predicting the toxicity of untested nonelectrolyte organic chemicals. The models need to be derived from a series of chemicals acting by a common molecular mechanism and encompass an adequate domain of spanned substituent space in their physical and chemical properties. The acute toxicity of many classes of nonelectrolytes is consistent with a narcosis or baseline toxicity mechanism. The ability to apply such models for predictive purposes also requires information to suggest that the candidate chemical acts by the same mechanism. 

The non-specific effects can be considered as the default mode of action, giving the minimal toxicity of any compound, and may be topped by specific effects that may be defined from clinical symptoms. Reactive toxicity has been ascribed to various interactions caused by a chemical s reactivity. Attempts to link the physico-chemical interactions with the physiological modes of action of toxicants have been successful so far only to a limited extent. The toxicity mechanisms attempt to deduce the compounds impacts to effects on the biochemical and biomolecular level. However, alike symptoms may result from different molecular interactions. The principal modes of action comprise ... 

Bar suggested that the toxicity in two-phase systems was caused by both the presence of a second phase (phase toxicity) and solvent molecules which dissolved in the aqueous phase (molecular toxicity). Basically, both mechanisms are governed by the same principle in that the solvent accumulates in the microbial membrane. In case of the direct contact between cells and pure solvent, the rate of entry of solvents in a membrane will be very high. If the solvent has to diffuse via the water phase, then the accumulation in membranes will be slower. This latter mechanism on the molecular toxicity has been investigated in more detail. In experiments with liposomes from E. coli, and ten representative organic solvents labeled by under aqueous-saturating levels, it was observed that the solvents accumulate... 

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