2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-induced reduction of adenosine deaminase activity in vivo and in vitro.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent immunosuppressant in several animal species. The purpose of this study was to determine if TCDD affected the activity of adenosine deaminase (ADA), a purine metabolizing enzyme that is vital to the proper functioning of the immune system. The effect of TCDD on ADA activity was studied in various tissues of male Balb/c mice (a TCDD-responsive strain) and DBA/2 mice (a less-responsive strain). Of the tissues examined after administration of TCDD in vivo (115 micrograms/kg, i.p.), ADA activity was found to be significantly reduced in thymic and splenic tissues of Balb/c mice at 24 hours postadministration. The enzyme activity in these affected tissues remained consistently low through 10 days postadministration. Such an effect of TCDD was both dose and time related in the thymic tissue of Balb/c mice. In contrast, no appreciable alterations in ADA activity were evident in any of the tissues of DBA/2 mice at any of the sampling intervals, indicating that such an effect of TCDD is likely to be mediated through the Ah receptor. This in vivo effect of TCDD on thymic ADA activity was also reproducible in situ where isolated whole thymuses were directly incubated with 10 nM TCDD. In this model, TCDD's effects on ADA activity were antagonized by known protein kinase or phosphorylation inhibitors such as quercetin, genistein, tyrphostin, and neomycin. These results indicate that the effect of TCDD on ADA activity in the thymus may be related to its property to elevate protein kinase activities in this tissue. ADA activity was also reduced in 3T3 cells that were treated with 10 nM TCDD in a low (1%) serum media. In contrast, 25 ng/mL epidermal growth factor (EGF) under such conditions consistently stimulated ADA activity. Interestingly, EGF at a similar concentration failed to elicit a stimulatory effect on ADA activity when cells were pretreated with TCDD. The property of TCDD to lower ADA activity under in vivo, in situ, as well as in vitro conditions appears to be largely related to its action to modulate protein phosphorylation activities.
Department of Environmental Toxicology, University of California, Davis 95616.
Muralidhara
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Matsumura
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Blankenship
D016475:3T3 Cells / Q000187:drug effects; D000243:Adenosine Deaminase / Q000378:metabolism*; D000818:Animals; D002396:Catechols / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology; D019833:Genistein; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D007529:Isoflavones / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009355:Neomycin / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000633:toxicity*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011794:Quercetin / Q000494:pharmacology; D013045:Species Specificity; D013154:Spleen / Q000187:drug effects / Q000201:enzymology*; D013950:Thymus Gland / Q000187:drug effects / Q000201:enzymology*; D020032:Tyrphostins
D002396:Catechols; D007529:Isoflavones; D009570:Nitriles; D000072317:Polychlorinated Dibenzodioxins; D020032:Tyrphostins; C060152:tyrphostin 47; D004815:Epidermal Growth Factor; D011794:Quercetin; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D000243:Adenosine Deaminase; D009355:Neomycin