| 8035742 |
Soleo L: [The detoxification pathways of electrophilic intermediate compounds] . Med Lav. 1994 Jan-Feb;85(1):22-36.
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. |
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