Identification of Intratissue Sites for Xenobiotic Activation and Detoxication

Abstract

It is now apparent that the generation of reactive metabolites from a multitude of xenobiotics frequently preceeds the appearance of necrosis, mutagenesis, carcinogenesis, and other cytotoxicities (Mitchell et al., 1976; Boyd, 1980; Wright, 1980; Miller and Miller, 1981, 1982; Boyd and Statham, 1983). It is also evident, however, that xenobiotics that are biotransformed into reactive metabolites usually exert relatively selective toxic effects within most mammalian tissues, i.e., they often damage either a specific morphological cell type or groups of morphologically similar cells located within selected areas or regions of tissues (Mitchell et al., 1976; Rappaport, 1979; Boyd, 1980; Baron and Kawabata, 1983; Minchin and Boyd, 1983). Differential susceptibility of cells to toxicity that results as a consequence of the formation of reactive metabolites undoubtedly is related to differences in the ability of cells to both activate and detoxicate xenobiotics (Boyd, 1980; Baron and Kawabata, 1983; Minchin and Boyd, 1983). Primarily for this reason, the intratissue localizations and distributions of cytochrome P-450 isozymes, NADPH-cytochrome P-450 reductase, epoxide hydrolase, glutathione S-transferases, and other enzymes that participiate in the activation and detoxication of xenobiotics recently have come under intensive investigation. Such investigation however, has been hindered greatly by the heterogeneous nature of most mammalian tissues, as well as by the fact that morphologically similar cells, hepatocytes for example, can exhibit significant differences in their ability to metabolize xenobiotics (Wattenberg and Leong, 1962; Gangolli and Wright, 1971; Ji et al., 1981; Conway et al., 1982; Baron and Kawabata, 1983).