title: Alteration of methylcholanthrene-mediated suppression of cutaneous delayed hypersensitivity by benzoflavone treatment of C57BL/6J mice.
abstract: The potential role of the cytochromes P-450 in methylcholanthrene (MC)-mediated suppression of cutaneous delayed hypersensitivity (CDH) in C57BL/6J (B6) mice was evaluated indirectly by treating mice with agents known to induce or inhibit hepatic cytochromes P-450 prior to contact sensitization. Subsequent alterations in aryl hydrocarbon hydroxylase (AHH) activity and CDH, as measured by suppression of 2,4-dinitrofluorobenzene (DNFB)-induced ear swelling, were measured. MC administration resulted in a dose-dependent suppression of ear swelling and a concomitant dose-dependent induction of hepatic AHH activity. Treatment of B6 mice with phenobarbital (PB), 80 mg/kg daily X 3, a broad spectrum inducer of P-450, resulted in a 2.5-fold increase in benzo[a]pyrene (B[a]P) hydroxylase activity without affecting CDH. Animals treated with the same PB protocol prior to an ED20 dose of MC showed no difference in suppression of CDH compared to animals treated with MC alone. In contrast, successive treatment with the selective P1-450 inducer, 5,6-benzoflavone (beta NF), prior to and following an ED20 dose of MC significantly increased suppression of CDH (p less than 0.001) usually seen at this MC dose. Treatment with a known inhibitor of cytochrome P1-450 activity, 7,8-benzoflavone (alpha NF), did not prevent AHH induction when administered prior to and following MC (ED100) nor did it suppress CDH when administered alone. However, this alpha NF treatment completely prevented suppression of CDH usually seen at this MC dose. These data provide evidence suggesting that metabolic activation by cytochrome P1-450 is required for the expression of the immunosuppressive activity of MC.
authors.affiliation: Division of Pediatric Pharmacology and Critical Care, Rainbow Babies and Childrens Hospital, Cleveland, Ohio.
authors.forename: D M
authors.initials: DM
authors.lastname: Frank
authors.forename: J L
authors.initials: JL
authors.lastname: Blumer
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001571:Benzoflavones / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004139:Dinitrofluorobenzene / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004342:Drug Hypersensitivity / Q000517:prevention & control; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D006968:Hypersensitivity, Delayed / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008748:Methylcholanthrene / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D010634:Phenobarbital / Q000494:pharmacology; D011083:Polycyclic Compounds / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000378:metabolism; D019324:beta-Naphthoflavone
chemical_list: D001571:Benzoflavones; D065607:Cytochrome P-450 Enzyme Inhibitors; D005419:Flavonoids; D007166:Immunosuppressive Agents; D011083:Polycyclic Compounds; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D008748:Methylcholanthrene; C011512:alpha-naphthoflavone; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D004139:Dinitrofluorobenzene; D001189:Aryl Hydrocarbon Hydroxylases; D010634:Phenobarbital