alpha-Naphthoflavone antagonism of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced murine lymphocyte ethoxyresorufin-O-deethylase activity and immunosuppression.
Suppression of murine humoral immunity by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to occur in vivo and in vitro. Studies have indicated that suppression of humoral immunity is mediated by the Ah receptor. Data presented in this paper demonstrate that alpha-naphthoflavone (ANF) and beta-naphthoflavone (BNF), like TCDD, bind to rat and murine hepatic and murine splenocyte cytosolic Ah receptor. Furthermore, BNF induces cytochrome P1-450 monooxygenase activity as measured by ethoxyresorufin-O-deethylase (EROD) in murine spleen cells to the same extent as TCDD. In contrast, ANF predominantly acts to antagonize TCDD induction of splenocyte EROD activity. Examination of humoral immunity in vitro demonstrated that BNF, like TCDD, is suppressive. Whereas ANF is suppressive at cytotoxic concentrations, lower concentrations of ANF antagonize the suppressive effect of TCDD. Antagonism by ANF of TCDD-induced EROD activity and suppression of humoral immunity occur at similar concentrations. These data suggest that ANF blocks TCDD suppression of B lymphocyte differentiation by competing with TCDD for binding to the Ah receptor. Since the mechanism of TCDD toxicity is not fully understood, probes such as ANF may be of great use in examining the role of the Ah receptor in mediating toxicity.
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D001571:Benzoflavones / Q000494:pharmacology*; D019363:Cytochrome P-450 CYP1A1; D003600:Cytosol / Q000378:metabolism; D004147:Dioxins / Q000037:antagonists & inhibitors*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D007165:Immunosuppression Therapy; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D010088:Oxidoreductases / Q000096:biosynthesis*; D000072317:Polychlorinated Dibenzodioxins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000378:metabolism
D001571:Benzoflavones; D004147:Dioxins; D005419:Flavonoids; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; C011512:alpha-naphthoflavone; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1