Identification of intratissue sites for xenobiotic activation and detoxication.

Results of immunohistochemical and histochemical investigations on xenobiotic-metabolizing enzymes and aryl hydrocarbon hydroxylase activity have demonstrated that xenobiotic activation and detoxication do not occur uniformly throughout the liver, skin, respiratory tract, and pancreas, four tissues that are targets for the toxic actions of xenobiotics that are biotransformed into reactive metabolites. It has been shown that there can be significant differences in the levels and activities of xenobiotic-metabolizing enzymes among even morphologically similar cells, that an inducer can affect a specific xenobiotic-metabolizing enzyme to significantly different extents within different cells in a tissue, and that inducers of xenobiotic-metabolizing enzymes can alter differentially the extents to which different cells within a tissue participate in xenobiotic metabolism. These studies also have revealed that the route of administration of an inducer can affect significantly the induction of xenobiotic-metabolizing enzymes and aryl hydrocarbon hydroxylase activity within an organ such as the pancreas. Some of the immunohistochemical findings reported for the cellular localizations of xenobiotic-metabolizing enzymes within specific tissues, e.g., the nasal mucosa, may not appear to be entirely consistent with the intratissue distribution of benzo[a]pyrene hydroxylase activity, especially after induction. However, it must be appreciated that other cytochrome P-450 isozymes undoubtedly are present within these tissues which, although not studied, also are capable of catalyzing aryl hydrocarbon hydroxylase activity.