Carcinogenic Chemicals metabolic reactions

Moreover, certain materials that apparently exist at subtoxic levels in the workplace can substantially appreciate in toxicity by undergoing chemical reactions within the body. For example, a metabolic reaction occurs in the case of benzidine dyes. The carcinogenic nature of benzidine has been recognized for many years, but benzidine-based dyes have been considered relatively safe on the assumption that they contain very little free or unreacted benzidine. Studies of analyses of urine samples collected from workers exposed to these dyes, however, indicate that metabolization of benzidine dye results in significantly elevated benzidine levels within the body. 

In this review, the chemical properties of these electrophilic metabolites (i-XIIl) are discussed in terms of their metabolic formation and reactivity with nucleophiles, solvolysis and redox characteristics, reaction mechanisms, and their role as ultimate carcinogenic metabolites. 

The metabolic formation of N-sulfonyloxy-N-acetyl-2-aminofluorene (N-sulfonyloxy-AAF) and its observed electrophilic reactivity, provided the first evidence for the importance of enzymatic conjugation reactions in chemical carcinogenesis (23,24). This reaction was shown to be catalyzed by PAPS-dependent sulfotrans-ferases that are located predominantly in liver cytosol and has been subsequently demonstrated for N-hydroxy arylamide metabolites of several other carcinogens, including N-acetyl-4-aminobiphenyl (AABP), benzidine, N-acetyl-2-aminophenanthrene and phenacetin. 

Carcinogen a substance that causes cancer Catabolism metabolic processes where molecules are broken down Catalysis chemical process in which a reaction rate is accelerated Catalyst a substance used to accelerate a chemical reaction without taking part in the reaction... 

Vinyl chloride is a chemical used in the manufacture of plastics, which is carcinogenic and causes various toxic effects, including liver injury and damage to the bones and skin. Liver hemangiosarcomas are produced in animals and humans. Vinyl chloride undergoes metabolic activation by cytochrome P-450 to an epoxide, which may interact with DNA and form adducts (ethenodeoxyadenosine and ethenodeoxycytidine), which leads to mutations. These can be detected in white cells, and a mutant p21 ras protein can be detected in the serum of exposed workers. Also, reaction with GSH occurs. 

Chemical carcinogens are not generally directly acting per se but are metabolically activated to electrophilic derivatives which are believed to be the actual initiators of the carcinogenic process ( 1). The electrophilic derivatives are extremely reactive and it is difficult, if not impossible, to monitor their production directly in biological systems. However, their formation can be monitored by analyzing the products of their reaction with DNA. 

The most important conclusion to be made from these studies is the great importance of hydrophobicity in the modulation of the potential for mutagenicity and carcinogenicity. Hansch and coworkers have showed that compounds that require S9 activation to become mutagenic in bacteria all have log Kow terms with coefficients near 1.0 (Debnath et al., 1994). Other QSARs show that where a direct chemical reaction with DNA appears to occur, without metabolic activation, no hydrophobic term enters into the equation (Hansch et al., 2001). In these cases, usually only the electronic (reactivity) properties are important. Notable examples of QSARs based on electronic terms and without a hydrophobic term relate to the mutagenicity to Salmonella of aniloacridines, di-platinum analogs, lactones, and epoxides. All of these examples are for chemicals that do not require activation (Hansch et al., 2001). 

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