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 d rugs and other chemicals, many of which require activation to toxic me tabolites by drug-metabolizing enzymes. We compared the induction of d rug-metabolizing enzymes, including cytochrome P450 1A1 (CYP1A1) and a ldehyde dehydrogenase (ALDH), which are differentially expressed in va rious macrophage populations following treatment of F344 rats with the inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Kupffer cells, al veolar macrophages and splenic macrophages from TCDD-treated animals e xpressed elevated levels of inducible CYP1A1 as compared to other macr ophage 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. Immuno-r eactive protein and mRNA transcripts for CYP1A1 were not detectable in resident peritoneal macrophages or peripheral blood monocytes. Examin ation of aromatic hydrocarbon receptor (AhR) levels in macrophage popu lations suggests that the ability of TCDD to induce metabolic enzymes in specific cell types correlates well with AhR expression. In vivo ac tivation of macrophages, using either Bacillus of Calmette and Guerin, Mycobacterium tuberculosis (BCG) or polyinosinicipolycytidylic 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 maturation al stage rather than their activation state. The metabolism of xenobio tics to toxic intermediates by immune cells and its role in immunosupp ression are discussed.