Comparative assessment of metabolic enzyme levels in macrophage populations of the F344 rat.
The immune system is a direct target for toxic insult by a number of drugs and other chemicals, many of which require activation to toxic metabolites by drug-metabolizing enzymes. We compared the induction of drug-metabolizing enzymes, including cytochrome P450 1A1 (CYP1A1) and aldehyde dehydrogenase (ALDH), which are differentially expressed in various macrophage populations following treatment of F344 rats with the inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Kupffer cells, alveolar macrophages and splenic macrophages from TCDD-treated animals expressed elevated levels of inducible CYP1A1 as compared to other macrophage subpopulations or cells from control rats. TCDD treatment also resulted in increased ethoxyresorufin-O-deethylase (EROD) activity and total cytochrome P450 content in tissue-derived macrophages. Immunoreactive protein and mRNA transcripts for CYP1A1 were not detectable in resident peritoneal macrophages or peripheral blood monocytes. Examination of aromatic hydrocarbon receptor (AhR) levels in macrophage populations suggests that the ability of TCDD to induce metabolic enzymes in specific cell types correlates well with AhR expression. In vivo activation of macrophages, using either Bacillus of Calmette and Guérin, Mycobacterium tuberculosis (BCG) or polyinosinic:polycytidylic acid (Poly I:C), caused no significant alteration in the levels of induction of CYP1A1. ALDH-3 induction was similar in all macrophage populations examined. These studies indicate that macrophages, particularly those from portals of entry, may be induced to produce increased levels of specific enzymes, and the induction is dependent upon their maturational stage rather than their activation state. The metabolism of xenobiotics to toxic intermediates by immune cells and its role in immunosuppression are discussed.
Germolec
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DR
Environmental Immunology and Neurobiology Section, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Adams
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NH
Luster
M I
MI
D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000378:metabolism; D004790:Enzyme Induction; D005260:Female; D015151:Immunoblotting; D007728:Kupffer Cells / Q000187:drug effects / Q000201:enzymology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000201:enzymology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology; D008969:Molecular Sequence Data; D010088:Oxidoreductases / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D013154:Spleen / Q000166:cytology
D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D000444:Aldehyde Dehydrogenase