Intestinal toxic metabolites/carcinogens

Another consequence of biliary excretion is that the compound comes into contact with the gut microflora. The bacteria may metabolize the compound and convert it into a more lipid soluble substance which can be reabsorbed from the intestine into the portal venous blood supply, and so return to the liver. This may lead to a cycling of the compound known as enterohepatic recirculation which may increase the toxicity (figure 3,32). If this situation occurs the plasma level profile may show peaks at various times corresponding to reabsorption rather than the smooth decline expected. If the compound is taken orally, and therefore is transported directly to the liver and is extensively excreted into the bile, it may be that none of the parent compound ever reaches the systemic circulation. Alternatively the gut microflora may metabolize the compound to a more toxic metabolite which could be reabsorbed and cause a systemic toxic effect. An example of this is afforded by the hepatocarcinogen 2,4-dinitrotoluene discussed in more detail in Chapter 5. Compounds taken orally may also come directly into contact with the gut bacteria. For example, the naturally occurring glycoside cycasin is hydrolysed to the potent carcinogen methy... 

The amount of dietary protein influenced the carcinogenicity of DMH in rats and its conversion to mutagenic metabolites and toxicity in mice. Raising protein intake in rats raised the incidence of tumors of the inner ear and in the small and large intestines (17). The source of protein (vegetable or animal) had no effect on DMH intestinal carcinogenesis (20). 

Other factors that affect absorption from the GI tract include its microflora and food content. The microflora of the GI tract, particularly in the large intestine, can play important roles in the activation of chemicals to toxic, mutagenic, or carcinogenic metabolites and in detoxifying mechanisms. The GI tract microflora differ between species and the flora can be affected following the administration of oral antibiotics or poorly soluble compounds. The presence of food in the GI tract may cause the absorption of compound to be reduced, delayed, or increased, or it can have no effect. 

The tumorigenic effects of gentian violet in animals are probably mediated through a metabolite. It is demethylated in the liver and is reduced to leukogentian violet by intestinal microflora. Complete demethyla-tion produces leukopararosaniline, which is carcinogenic in rats. A free-radical derivative is also formed in the liver, but its toxicity is not clear N-demethylation by peroxidases and cyclo-oxygenase are other routes of metabolism [62 ]. 

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