Induction of CYP1A1 and ALDH-3 in lymphoid tissues from Fisher 344 rats exposed to 2,3,7,8-tetrachlorodibenzodioxin (TCDD).
The immune system is a primary target for toxic insult by a number of drugs and environmental 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), in lymphoid tissues of F344 rats following treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). ALDH was induced in both the spleen and the thymus after TCDD treatment, with maximal expression at 9 and 15 days, respectively. Thymic microsomal preparations from TCDD-treated animals expressed elevated levels of inducible CYP1A1 as compared to microsomes from the spleens of treated animals or tissues from control rats. TCDD treatment also resulted in increased ethoxyresorufin-O-deethylase (EROD) activity in the thymus. There were no detectable mRNA transcripts for CYP1A1 in peripheral blood or splenic lymphocytes from treated animals; however, CYP1A1 transcripts were induced in isolated thymocytes, whole spleen, and whole thymus. In vitro exposure to TCDD did not result in induction of immunoreactive CYP1A1 in thymocytes unless simultaneously activated with the mitogen, phytohemagglutinin (PHA). Immunohistochemical localization of CYP1A1 in immune tissues indicated that cells other than the lymphoid populations are responsible for the increased CYP1A1 expression. The pattern of CYP1A1 induction was related to the expression of the Ah receptor (AhR) in immune tissues. Western blot analyses demonstrated less AhR present in peripheral blood lymphoid cells and spleen, as compared to whole tissues. These studies indicate that while drug-metabolizing enzymes are present in immune tissues, the induction of enzymes is selective in different lymphoid cells.
Germolec
D R
DR
Environmental Immunology and Neurobiology Section, Naitonal Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, 27709, USA.
Henry
E C
EC
Maronpot
R
R
Foley
J F
JF
Adams
N H
NH
Gasiewicz
T A
TA
Luster
M I
MI
D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis*; D000818:Animals; D001483:Base Sequence; D002458:Cell Fractionation; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D015151:Immunoblotting; D007150:Immunohistochemistry; D007700:Kinetics; D008099:Liver / Q000737:chemistry; D008214:Lymphocytes / Q000187:drug effects* / Q000201:enzymology; D008221:Lymphoid Tissue / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology; D008861:Microsomes; D008969:Molecular Sequence Data; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D016133:Polymerase Chain Reaction; D051381:Rats; D011916:Rats, Inbred F344
D000072317:Polychlorinated Dibenzodioxins; D003577:Cytochrome P-450 Enzyme System; D000444:Aldehyde Dehydrogenase