In situ sites for xenobiotic activation and detoxication: implications for the differential susceptibility of cells to the toxic actions of environmental chemicals

The findings reported in this communication illustrate that histochemical approaches can provide a significant amount of insight into an area of considerable toxicologic importance. Results of our immunohistochemical and histochemical studies clearly demonstrate that neither xenobiotic-metabolizing enzymes nor oxidative xenobiotic metabolism occur uniformly throughout tissues that often are damaged as a result of the bioactivation of environmental chemicals and other xenobiotics, that there can be significant differences in both the contents and activities of xenobiotic-metabolizing enzymes among even morphologically similar cells such as hepatocytes, and that enzyme inducers can alter differentially the extents to which different cells in a tissue metabolize xenobiotics. Knowledge of the precise intratissue localizations and distributions of xenobiotic-metabolizing enzymes and xenobiotic biotransformation reactions clearly is critical for defining the roles individual cells play in the metabolism of xenobiotics. It must be recognized, however, that the mere presence of xenobiotic-metabolizing enzymes in a cell cannot, by itself, explain why that cell might be highly susceptible to toxicities resulting from the bioactivation of certain xenobiotics. Thus, it is apparent that considerably more study is needed, especially in situ using histologic and cytologic techniques, in order to characterize the balance between xenobiotic activation and detoxication processes within individual cells in target tissues and elucidate the basis for the cell-selective nature of toxicities caused by the generation of reactive metabolites from many xenobiotics.