Metabolic Activation of Xenobiotics: Ethylene Dibromide and Structural Analogs

Abstract

A large number of compounds which can enter living organisms are relatively harmless as such, but are transformed by the body into reactive agents. The structure of such a compound is the factor determining its disposition in the organism. Its physicochemical characteristics determine the overall fate in terms of absorption, distribution and excretion, while the chemical structure is the decisive factor in its biotransformation. Whether formation of reactive intermediates occurs depends on what points of attack it has to offer to the different enzyme systems. The extent to which alkylation of cellular macromolecules by reactive intermediates occurs in turn depends on the balance of activating and detoxifying enzymes in the particular cell and on the reactivity of the intermediates towards critical targets in the cell macro-molecules. Many chemicals undergo several concurrent metabolic pathways. The ratio between these pathways may be a decisive factor determining the extent of adverse effects caused by these chemicals. Small variations in structure may have a drastic effect on the activation and detoxification by competing enzyme systems. These concepts are elucidated using the examples of ethy-lene dibromide and some structural analogs. Apart from the parent compound itself, two alkylating species may be responsible for the toxic effects of these compounds. Bromo-acetaldehyde is formed by oxidation, catalyzed by cyto-chrome P-450, followed by spontaneous loss of hydrogen bromide; S-2-bromoethylglutathione results from replacement of a bromine atom by glutathione, catalyzed by the glutathione transferases. The latter intermediate possesses a reactivity comparable to sulfur mustard. Results indicate that the reactive glutathione conjugate is responsible for the mutagenic and possibly also the carcinogenic effect of ethy-lene dibromide. However, in vivo, oxidation is quantitatively much more important as a primary process.