Frank D M, Blumer J L
Division of Pediatric Pharmacology and Critical Care, Rainbow Babies and Childrens Hospital, Cleveland, Ohio.
Toxicol Appl Pharmacol. 1988 Aug;95(1):72-81. doi: 10.1016/s0041-008x(88)80009-7.
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.
通过在接触致敏前用已知可诱导或抑制肝细胞色素P-450的药物处理小鼠，间接评估了细胞色素P-450在甲基胆蒽（MC）介导的C57BL/6J（B6）小鼠皮肤迟发型超敏反应（CDH）抑制中的潜在作用。测量了随后芳烃羟化酶（AHH）活性和CDH的变化，通过抑制2,4-二硝基氟苯（DNFB）诱导的耳部肿胀来衡量。给予MC导致耳部肿胀的剂量依赖性抑制以及肝AHH活性的伴随剂量依赖性诱导。用苯巴比妥（PB），80mg/kg每日×3，一种P-450的广谱诱导剂处理B6小鼠，导致苯并[a]芘（B[a]P）羟化酶活性增加2.5倍，而不影响CDH。在给予ED20剂量的MC之前用相同的PB方案处理的动物与单独用MC处理的动物相比，在CDH抑制方面没有差异。相反，在ED20剂量的MC之前和之后连续用选择性P1-450诱导剂5,6-苯并黄酮（βNF）处理显著增加了通常在该MC剂量下所见的CDH抑制（p小于0.001）。用细胞色素P1-450活性的已知抑制剂7,8-苯并黄酮（αNF）处理，在MC（ED100）之前和之后给予时既不阻止AHH诱导，单独给予时也不抑制CDH。然而，这种αNF处理完全阻止了通常在该MC剂量下所见的CDH抑制。这些数据提供了证据，表明细胞色素P1-450的代谢激活是MC免疫抑制活性表达所必需的。
