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RESEARCH PRODUCT

Chapter 2: METABOLISM OF CARCINOGENS, POSSIBILITIES FOR MODULATION

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: One of the structural elements which are widely occurring in very many chemical mutagens and carcinogens are aromatic and olefinic moieties. These can be transformed into epoxides by microsomal monooxygenases. Such epoxides may spontaneously react with nucleophilic centers in the cell and thereby covalently bind to DNA, RNA and protein. Such a reaction may lead to cytotoxicity, allergy, mutagenicity and/or carcinogenicity, depending on the properties of the epoxide in question. An important contributing factor is the presence of enzymes controlling the concentration of such epoxides. There are several microsomal monooxygenases which differ in activity and substrate specificity. With large substrates, some monooxygenases preferentially attack at one specific site different from that attacked by others. Some of these pathways lead to reactive products, others are detoxification pathways. Also important are the enzymes which metabolize epoxides, such as epoxide hydrolases and glutathione transferases. Such enzymes can act as inactivating and in some specific cases also as co-activating enzymes. Moreover, precursor-sequestering enzymes such as dihydrodiol dehydrogenase, glucuronosyl transferases and sulphotransferases are important for the control of reactive epoxides. These enzymes themselves are subject to control by many endogenous and exogenous factors. By virtue of their contribution to the control of carcinogenic metabolites such modulators can act as modifiers of tumorigenesis and can be used experimentally to study the role of the various individual enzymes.