Carcinogens intestinal microflora metabolism

Goldin, B.R. (1990) Intestinal microflora metabolism of drugs and carcinogens. Annals of Medicine, 22, 43-48. 

Azo Compounds Azo dyes are widely used in the food, pharmaceutical, cosmetic, textile, and leather industry. They are synthetic compounds characterized by one (monoazo) or several intramolecular N = N bonds. Azo dyes, if they are systemically absorbed, can be metabolized by the way of azoreductases of intestinal microflora by liver cells and skin surface bacteria. This metabolism leads to aromatic amines that can be hazardous. In the 1930s, some azo derivatives like 4-dimethyl aminoazoben-zene (Butter Yellow, Cl Solvent Yellow 2, Cl 11020) and o-aminoazotoluene were experimentally found to be directly carcinogenic to liver and bladder after feeding. Other complex azo dyes like Direct Black 38 or Direct Blue 6 (Figure 28) release the aromatic amine benzidine. Some examples of azo dyes metabolized in benzidine and benzidine-congeners are listed in Table 3. 

C-labelled lithocholic acid sulphates, 27, found in both human and animal bile30,31, have been synthesized in a one-step32 sulphonation procedure (equation 11) to study the metabolic processes caused by human intestinal microflora and to make possible the identification of new mutagenic/carcinogenic products. Fecal bile lithocholic acid enhances liver and colon tumorigenesis. 

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 ]. 

The metabolism of nitro derivatives of PAHs is different from metabolism of the parent PAHs. Orally administrated compounds are mainly reduced to amino derivatives by intestinal microflora. Their elimination from the body occurs after oxidation to hydroxy derivatives and acetylation of amino group in the hver. Hydroxyni-tro derivatives of PAHs are the major products that are resorbed unchanged from the gastrointestinal tract. Estimation of risks from dietary intake of nitro-PAH derivatives has not been worked out in detail, with respect to the limited data on their occurrence in foods. Generally, these direct carcinogens require metabohc activation. Particularly intense mutagenic effects have been demonstrated in nitro derivatives of pyrene. 

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... 

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