Lead toxicity action mechanisms

A. Modes of Toxic Action. This includes the consideration, at the fundamental level of organ, cell and molecular function, of all events leading to toxicity in vivo uptake, distribution, metabolism, mode of action, and excretion. The term mechanism of toxic action is now more generally used to describe an important molecular event in the cascade of events leading from exposure to toxicity, such as the inhibition of acetylcholinesterase in the toxicity of organophosphorus and carbamate insecticides. Important aspects include the following ... 

Enzyme Inhibition/Activation. A major site of toxic action for metals is interaction with enzymes, resulting in either enzyme inhibition or activation. Two mechanisms are of particular importance inhibition may occur as a result of interaction between the metal and sulfhydryl (SH) groups on the enzyme, or the metal may displace an essential metal cofactor of the enzyme. For example, lead may displace zinc in the zinc-dependent enzyme 5-aminolevulinic acid dehydratase (ALAD), thereby inhibiting the synthesis of heme, an important component of hemoglobin and heme-containing enzymes, such as cytochromes. 

A. Mechanisms of toxic action - all events leading to adverse effects at the level of the organ, cell, or molecular function... 

For example, the induction of metabolizing enzymes by a chemical can greatly modify its PK and that of other substances, which is the subject of metabolic interactions [59], Intestinal barrier alterations due to intestinal toxicity can also affect PK [3]. Toxicity-induced retro-action mechanisms can also increase volumes of distribution The interaction of a chemical with aromatase can lead to a decrease in estradiol production and hence a decrease in FSH secretion, followed by a decrease in follicular growth and a reduction of the ovary volume [56], This should have implications for the design of in vitro assay systems. Integrated systems, such as those coupling metabolism and effect observations in human on chip micro-devices [5], offer a way to model experimentally the PK/PD continuum. 

Estimation of Risk. The estimation of risk contains uncertainties, based on the lack of specific data (such as exposure information) and/or the lack of understanding of the mechanism of toxic action of a compound. Between the extremes of acturial risk, which is based on enough information that "time has removed the uncertainty," such as the probability of death as cited in an insurance table, and theoretical risk, which is based on probabilistic calculations of events which have never actually occurred (e.g., nuclear "winter" (7)) lies a wide continuum into which most estimates of human health effects fall. In real-life situations, many assumptions are made in evaluating risk in order to make a conclusion, and these assumptions lead to uncertainties in the final result. These uncertainties should be understood as limitations to the best guess science can presently make. Although one response to this uncertainty, in the face of an outcome as fearsome as cancer, is to deny that there is a lack of certainty, the more reasonable response is to try to estimate the uncertainty, making it clear that any estimate is bracketed by these possible errors. 

The versatility of the P450 oxygenases is summarized in Figure 9.3. Epoxides can be introduced into aromatic rings or across double bonds. The former reaction leads to a hydroxy or dihydodiol. It is most unlikely to observe aldrin in environmental samples since it is rapidly converted to dieldrin, a common environmental contaminant that is very stable. Aliphatic chains can be hydroxylated and ethers, thioethers, and substituted amines dealkylated. The conversion of parathion to the more reactive paraoxon is a factor in the mechanism of toxic action, as well as its environmental stability (see Hydrolysis, Chapter 8). The situation can be complicated by the fact that a substrate can often undergo more than one reaction. 

Analysis of the biochemical aspects of organ specificity in toxic action (by Dr. J. S. Dutcher) began with a survey of the factors that influence patterns of organ-specific toxicity. Notable among these are the mechanisms of detoxication and metabolic activation, leading to covalent interaction with cellular macromolecules and consequent toxicity. 

The plasma membrane of cells is one of the main targets for toxic metals, such as lead and zinc. However, the ceU mechanisms of toxic action of these metals are not completely clear. Therefore, a study of the fine structure of erythrocyte membranes under the action of toxic and potentially toxic metal ions is of major... 

Fig. 5 Generic mechanism of AhR-mediated toxicity AhR mediates signal transduction by dioxin-like ligands, which form a transcription factor complex with an aryl hydrocarbon nuclear translocator protein (ARNT). This heterodimer recognizes specific DNA sequences, namely dioxin responsive elements (DREs), and leads to induction of several genes forming the so-called Ah gene battery. In this process, the elevated levels of the protein products are assumed to be involved in the toxic action of AhR ligands. AIP AhR inhibitory protein, hsp90 90-kDa heat shock protein, ARNT AhR nuclear translocator, XRE xenobiotic response element, CYPIA eyto-chrome P450 lA gene/protein (adapted from [211, 212])...

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