Cell- and tissue-specific metabolic activation of chemicals as determined by autoradiography: in vitro-in vivo correlations.
Numerous chemicals require metabolic activation to exert toxicity. Such metabolism-dependent toxicity may be due to the formation of electrophiles that bind irreversibly to cellular macromolecules in the vicinity of their site of formation. A high cellular concentration of a covalently bound metabolite may thus imply a target site for toxicity. Autoradiography at different levels of resolution is useful to determine cell-specific covalent metabolite binding of radiolabelled chemicals, both in vivo and in vitro. Using this approach, cell-specific toxicants such as dichlobenil (olfactory mucosa) and MeSO(2)-DDE (adrenal cortex) have been identified. In addition, unforeseen sites of local metabolism of toxic chemicals have been demonstrated. In our experience, the in vitro-in vivo correlations are often good, while in some cases results obtained in vivo cannot be reproduced in vitro. The inability of tissue slices to account for in vivo events may depend on metabolism in non-target tissues and differences in tissue disposition in vivo and in vitro. Examples are given to demonstrate the utility of autoradiography in vitro and in vivo to trace metabolism-dependent binding and toxicity in airway epithelia, vascular endothelia and adrenal zona fasciculata cells.
Brittebo
E B
EB
Department of Pharmaceutical Biosciences, Division of Toxicology, Box 594, S-751 24, Uppsala Sweden.
Brandt
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