Liver foreign compound toxicity

Smith, M. T., Thor, H., and Orrenius, S. (1983). The role of lipid peroxidation in the toxicity of foreign compounds to liver cells, Biochem. Pharmacol., 32, 763-764. 

Distribution. The distribution of foreign compounds may vary between species because of differences in a number of factors such as proportion and distribution of body fat, rates of metabolism and excretion and hence elimination, and the presence of specific uptake systems in organs. For instance, differences in localization of methylglyoxal-bis-guanyl hydrazone (Fig. 5.6) in the liver account for its greater hepa to toxicity in rats than in mice. The hepatic concentration in mice is only 0.3% to 0.5% of the dose after 48 hours, compared with 2% to 8% in the rat. 

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. 

The kidney is an important organ for the excretion of toxic materials and their metabolites, 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 liver has as one of its functions the metabolism of foreign compounds some pathways result in detoxification and others in metabolic activation. Also, the liver may serve as a route of elimination of toxic materials by excretion in bile. In addition to the liver (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. 

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... 

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