A brief description is given of the chemical characteristics on which depend the particular reactivity of electrophilic substances that makes them bind via a covalent bond with nucleophilic sites of cellular macromolecules. The electrophilic intermediates that are of greatest importance for chemical
carcinogenesis are examined. The metabolic routes of detoxification are discussed. The main route is the oxidative route, which uses the
enzyme epoxide hydrolase. Another route consists of conjugation of intermediate electrophiles with
glutathione reduced via a
glutathione-S-transferase or spontaneously. The conjugated
glutathione compounds are then further biotransformed and eliminated via the urine as mercapturic
acids. In the case of
styrene the author's experience with exposed workers showed that about 6-8% of inhaled
styrene is eliminated in the form of mercapturic
acids. For
acrylonitrile the route of conjugation with
reduced glutathione is the main detoxification route. A study by the author on rats showed that for concentrations up to 15 mg/kg
body weight 73% of
acrylonitrile administered intraperitoneally is eliminated as cyanoethylmercapturic
acid, derived from the direct conjugation of
acrylonitrile with
glutathione. Detoxification of the radical species occurs via cellular constituents, such as
reduced glutathione, and via
enzymes, such as
superoxide dismutase, GSH
peroxidase,
catalase. These
enzymes protect the liver from the action of
free radicals that are produced during oxidative metabolism of
ethanol. The differences in metabolic routes of detoxification among species as causes of hypersusceptibility to develop
cancer are discussed. In the case of
1,3-butadiene the greater susceptibility of the mouse to develop tumours compared with the rat is due to the fact that the mouse is capable of oxidizing
butadiene to epoxybutene more rapidly, has a more rapid saturation of epoxyhydrolase and a faster consumption of non proteic sulphidrylic groups, so that epoxybutene, because it cannot be metabolized, tends to bind with the cellular macromolecules thus producing damaging effects. Also in the case of
methylene chloride, the greater susceptibility of the mouse to develop tumours compared with the rat seems to be connected with a greater production of S-chloromethyl-GSH in the mouse, although no specific oncogenic action has yet been demonstrated for this reactive intermediate.