Kidney foreign compound toxicity

The kidney is an important organ for the excretion of toxic materials and their metaboHtes, and measurement of these substances in urine may provide a convenient basis for monitoring the exposure of an individual to the parent compound in his or her immediate environment. The Hver has as one of its functions the metaboHsm of foreign compounds some pathways result in detoxification and others in metaboHc activation. Also, the Hver may serve as a route of elimination of toxic materials by excretion in bile. In addition to the Hver (bile) and kidney (urine) as routes of excretion, the lung may act as a route of elimination for volatile compounds. The excretion of materials in sweat, hair, and nails is usually insignificant. 

Many toxic substances and other foreign compounds are removed from the blood as it passes through the kidneys. The kidneys receive around 25% of the cardiac output of blood, and so they are exposed to and filter out a significant proportion of foreign compounds. However, excretion into the urine from the bloodstream applies to relatively small, water-soluble molecules large molecules such as proteins do not normally pass out through the intact glomerulus, and lipid-soluble molecules such as bilirubin are reabsorbed from the kidney tubules (Fig. 3.31). 

Although the CYP enzymes are the most abundant in the liver, they are also present in other tissues including the skin, kidney, intestine, lung, placenta, and nasal mucosa. Because CYP exists as multiple isozymes with different substrate specificities, the presence or absence of a particular CYP isozyme may contribute to tissue-specific toxicities. Many drugs and other foreign compounds are known to induce one or more of the CYP isozymes, resulting in an increase, decrease, or an alteration in the metabolic pathway of chemicals metabolized by the CYP isozymes involved. Specific examples of these types of interactions are given later in this section. 

Numerous foreign compounds enter a body in the course of time. This could be through inhalation, skin adsorption or, more importantly, the diet. Hydrophilic compounds can be easily excreted through bile in the faeces or through the kidney into the urine. The more lipophilic compounds are not so readily excreted and tend to accumulate in the fatty tissues of the body. This may lead to elevated and thereby toxic levels. Therefore excretion is preferable. To enhance this excretion, the molecule has to be made more hydrophilic. This process is called biotransformation. 

The liver is a prime target for toxicity because all chemicals received orally are carried directly to the liver by the hepatic portal vein, immediately after absorption. As mentioned, liver cells have an astounding capacity to metabolize these foreign compounds, in most instances turning them into water-soluble forms that can be readily excreted from the body (through the kidney). But this detoxification... 

Many toxic substances and other foreign compounds are removed from the blood as it passes through the kidneys. The kidneys receive around 25 % of the cardiac output of blood and so they are exposed to and filter out... 

As discussed in the preceding chapter, foreign and potentially toxic compounds absorbed into biological systems are generally lipophilic substances. They are therefore not ideally suited to excretion, as they will be reabsorbed in the kidney or from the gastrointestinal tract after biliary excretion. For example, highly lipophilic substances such as polybrominated biphenyls and DDT are poorly excreted and therefore may remain in the animal s body for years. 

If, following absorption, medications were undisturbed by the body, we would need to take only one dose for an eternal effect. Of course, this is not the case. As soon as drugs enter the bloodstream, the process of metabolism ensues. The body recognizes the drug as a foreign substance and eliminates it outright (say, via the kidneys, as in the case of lithium) or transforms it chemically, using a complex enzyme mechanism located in the liver. This chemical transformation enables the medication to be eliminated from the body. In some cases, the chemical transformation produces a new compound that may also have therapeutic effects (or, in some rare instances, a toxic effect). For example, fluoxetine (trade name Prozac) is transformed into norfluoxetine, which is also an antidepressant. A similar situation occurs with the old tricyclic antidepressants (amitriptyline—trade name Elavil—to nortriptyline the latter, in fact, is... 

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