Target Organ Toxicity

Although any organ or tissue may be a target for a toxic compound, such compounds often damage specific organs. Therefore it is instructive first to examine the principles underlying the susceptibility of certain organs to damage by toxic substances.

Thus, there are a number of different reasons why an organ might be a target: a its blood supply b the presence of a particular enzyme or biochemical pathway c the function or position of the organ d the vulnerability to disruption or degree of specialization e the ability to repair damage f the presence of particular uptake systems g the ability to metabolize the compound and the balance of toxication/detoxication systems h binding to particular macromolecules.

Thus, those organs well supplied with blood such as the kidneys will be exposed to foreign compounds to a greater extent than poorly perfused tissue such as the bone. Therefore, factors which affect the absorption, distribution and excretion of foreign compounds and the physicochemical characteristics of those compounds can all affect the toxicity to particular target organs. Those organs which are metabolically active such as the liver may be more vulnerable than metabolically less active tissues such as the skin. This is due to the fact that many compounds require metabolic activation in order to be toxic (see Chapter 4, figure 4.67 and Chapter 7). However the toxicity to the organ will depend on the balance of toxication and detoxication pathways and other factors such as the ability to repair toxic damage. Thus, although the liver may have the greatest metabolic activity if this extends to detoxication pathways as well as toxication pathways, overall the toxicity may be less than in an organ which has lower activity for the toxication pathway, but lacks the detoxication pathway. Organs or tissues which are at sites of entry such as the gastrointestinal tract may be exposed to higher concentrations of foreign compounds prior to dilution by blood and other fluids, and hence may be more susceptible than deep tissues such as muscle. Such tissues as the skin, gastrointestinal tract and lungs may suffer local irritation as they tend to be exposed to substances as a result of their position and function. Highly specialized and vital organs such as the central nervous system (CNS) are susceptible to disruption and are not easily repaired in comparison with adipose tissue, for example, which is less vital and less specialized. Uptake into and concentration of foreign compounds by some organs, in some cases such as the kidney and liver as a result of excretory function, may impart vulnerability. Binding to specific macromolecules such as melanin in the eye, for example, may lead to target organ toxicity. Some of the interrelationships between metabolism, distribution and excretion which may affect toxicity are shown in figure 6.1.

FIGURE 6.1 The interrelationships between the disposition and toxicity of a foreign compound. The parent compound may undergo distribution out of the blood (d) to other tissues and there cause toxicity by reaction with receptors

(r). Alternatively metabolism (m) may also occur and give rise to toxic metabolites (a) which react with critical targets (r). Metabolites may also distribute back into the blood (b) and be excreted (e).

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Thus, the distribution of the parent compound or metabolite(s) into the target tissue(s), metabolism and excretion in such tissues and the interaction with receptors or other critical cellular macromolecules are all dynamic processes occurring at particular rates. Factors which affect these processes therefore will influence toxicity and the particular target organ, and may even change the target organ. Thus, it is clear from figure 6.1 that if the parent compound is toxic, factors such as enzyme induction or inhibition which change metabolism (m) or change distribution to tissues (d) or excretion (e) will tend to change the toxicity. This is provided that the toxic response is dose-related. Specific uptake systems will influence the distribution (d) and specific excretory routes (e) may be saturated. Metabolism may cause the appearance of another, different, type of toxicity. If a metabolite is toxic then factors which increase metabolism may increase the toxicity, provided that detoxication pathways (b) are not also increased and therefore compensate. However, the presence or absence of such pathways (b) may determine whether a tissue becomes the target. Toxic metabolites or proximate toxic metabolites may be produced in one organ such as the liver and transported to another (dm). The interaction of toxic or reactive metabolites with receptors (r) may be tissue specific and there may be protective agents such as glutathione in some tissues. These principles are further exemplified in this section with regard to the various target organs considered, and also in the final chapter with specific examples of toxic compounds.

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