Sites for xenobiotic activation and detoxication within the respiratory tract: implications for chemically induced toxicity.
Results of in situ immunohistochemical investigations on several enzymes which participate in the bioactivation and detoxication of xenobiotics and of histochemical studies on aryl hydrocarbon hydroxylase activity summarized in this report clearly demonstrate that there are numerous sites within the respiratory tract at which xenobiotics can be bioactivated and detoxicated. The data presented, however, also reveal that xenobiotic-metabolizing enzymes and benzo[a]pyrene hydroxylase activity may not be distributed uniformly within individual segments (e.g., the nasal mucosa) of this organ system. Thus, it should be apparent from these findings that one cannot generalize as to how a given xenobiotic-metabolizing enzyme or xenobiotic monooxygenase activity normally is distributed either within or among the different segments of the respiratory tract. Additionally, since enzymes catalyzing the bioactivation and detoxication of xenobiotics usually are present within the same respiratory tract cells, it obviously is difficult to predict from these results which cell types within individual segments of this organ system most likely would be damaged as a consequence of exposure to xenobiotics which are biotransformed into cytotoxic metabolites by cytochrome(s) P-450. Although the cellular localizations and intercellular distributions of cytochromes P-450 BNF-B and MC-B parallel those of benzo[a]pyrene hydroxylase activity within the different segments of the respiratory tract in untreated rats, immunohistochemical findings on the inductions of these cytochrome P-450 isozymes are not entirely consistent with histochemical observations on the enhancement of benzo[a]pyrene hydroxylase activity by Aroclor 1254 within the nasal mucosa and by both Aroclor 1254 and 3-methylcholanthrene within the lung. It must be appreciated, however, that other cytochrome P-450 isozymes undoubtedly are present and inducible in the nasal mucosa and lung and, further, that these hemeproteins, although being immunochemically unrelated to the cytochrome P-450 isozymes studied, also could catalyze aryl hydrocarbon hydroxylase activity. Nevertheless, these immunohistochemical and histochemical findings do demonstrate that one cannot generalize as to how chemicals which induce the same xenobiotic-metabolizing enzyme will affect that enzyme within different segments of the respiratory tract and, moreover, that inducers of cytochromes P-450 can alter differentially the extents to which different cells within a given segment of the respiratory tract (e.g., the nasal mucosa) participate in the oxidative metabolism of xenobiotics.
Baron
J
J
Department of Pharmacology, University of Iowa College of Medicine, Iowa City 52242.
Burke
J P
JP
Guengerich
F P
FP
Jakoby
W B
WB
Voigt
J M
JM
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D008658:Inactivation, Metabolic; D008168:Lung / Q000201:enzymology; D009297:Nasal Mucosa / Q000201:enzymology; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D012137:Respiratory System / Q000187:drug effects / Q000378:metabolism*; D014132:Trachea / Q000201:enzymology
D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases