We can distinguish between the mechanism of toxicity and the toxic effect. The toxic effect is the adverse reaction that is observed, whereas the mechanism is the underlying process that leads to the effect. Put another way, the mechanism is the cause, usually at the molecular level, and the effect is the result. In some cases, as in biochemical effects, the distinction can be arbitrary.
Ultimately, toxins act by reacting with specific compounds in the organism. The result may be an alteration to a metabolite, enzyme, or cell structure. The site where the toxin acts is called the target tissue or target organ. The specific compounds in the target tissue that the toxins react with are called receptors. Organs vary in their sensitivity because they may differ in numbers or types of receptors, toxin transport, or organ function. For example, neurons depend on mitochondrial activity for their ATP and are therefore more sensitive to substances, such as carbon monoxide, that affect oxygen transport. The liver and kidney receive more blood than do other organs, making them a frequent target. Rapidly dividing cells such as bone marrow and intestinal mucosa are more sensitive to genotoxins.
Some toxins are relatively nonselective; they exert their effect on any tissue they contact. This tends to be the case for more highly reactive toxins, such as strong oxidizers, irritants, or free-radical producers. Even nonselective toxins, however, can exert their damage selectively either at the tissue first contacted or at other susceptible tissues. This may be the mode of action for chemical disinfectants such as chlorine.
Biochemical changes may be reversible or irreversible. Physicochemical interactions tend to be reversible. Examples include carbon monoxide poisoning of hemoglobin and narcosis induced by hydrophobic solvents. Covalent bonding and degradation reactions between toxins and cellular substances are more likely to be irreversible. Examples are the bonding of mercury, lead, and cadmium to sulfhydryl (— SH) groups in proteins, and the damage to lung cell components by ozone.
Covalent Bonding Examples of toxicity due to covalent bonding include protein denaturing by heavy metals and the interference of cyanide and sulfide with the cytochrome system. Mercury, lead, and cadmium bond to sulfhydryl (—SH) groups in proteins. Since these groups are important in protein folding, this causes denaturing of proteins, leading to profound effects. HCN and H2S bond to iron in cytochromes. This halts the electron transport system, which is responsible for most of the energy yield of respiration. Others examples, which are described further below, are the reaction of pesticides with the enzyme acetylcholinesterase and reactions involving cellular DNA.
Physicochemical Bonding Bonds between toxins and cellular substances involving van der Waals, hydrogen, and polar bonds also create toxic effects by modifying normal biochemical function. Examples are the complexation of metals and the effect of solvents on plasma membranes.
Multiple physicochemical bonds with a single molecule or complex is called chelation. Chelation can alter the distribution of substances, especially heavy metals, by effectively changing their physicochemical behavior (solubility, lipophilicity, etc.). This can affect excretion or can sequester substances within the organism. Enzyme activity can be susceptible to this chelation since many enzyme cofactors are inorganic metals.
For example, the solvent carbon disulfide, CS2, reacts with amino acids to form thiazolidone and thiocarbamate compounds, which chelate zinc. Rats exposed to CS2 rapidly lost Zn in the urine due to the increased solubility of the complex. Thiozolidone is also thought to make copper less available as an enzyme cofactor. The complexing agent ethylenediaminetetraacetic acid (EDTA) is used in cases of lead poisoning to hasten excretion of that toxic metal.
A phenomenon called metal shift is the effect in which a toxicant causes metals to decrease in one set of organs and increase in another. For example, feeding vanadium to rats at levels below 150 ppm resulted in iron moving into the liver and spleen, whereas above 250 ppm it caused iron concentrations in those organs to fall as low as one-third of the normal content. Metal shift might be caused by chelation or competitive absorption.
Enzyme Disruption The normal action of enzymes can be disrupted in a number of ways. A toxin can bind, reversibly or irreversibly, to the active site or the binding site of a cofactor, or it may bind elsewhere, causing conformational changes affecting the active site. The toxin can also have its effect by reacting directly with a cofactor, changing its reactivity or availability. For example, fluoride inhibits enolase, one of the enzymes of glycolysis, presumably by complexing with its Mg2+ cofactor. Finally, a toxin may mimic a metabolite or cofactor, competing with the normal metabolite for the active site. This is the case with fluorocitrate, as described in Section 18.5.
An interesting comparison of effects occurs with two classes of insecticides, both of which affect the same enzyme, one irreversibly and the other reversibly. Both of these classes form covalent bonds with the neurotransmitter-degrading enzyme acetylcholines-terase, inhibiting it (Figure 17.1). Symptoms produced are muscular twitching, weakness, and ultimately paralysis. One class, the organophosphates, forms bonds that are practically irreversible. Carbamate insecticides, on the other hand, bond to the same enzyme
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