Kudo S, Kawano K
Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Japan.
J Interferon Cytokine Res. 1999 Jun;19(6):601-7. doi: 10.1089/107999099313730.
The effect of recombinant human interleukin-1beta (IL-1beta) on the modulation of hepatic cytochrome P450 (P450) was investigated by in vivo subcutaneous dosing studies in male Sprague-Dawley rats. To assess the effect of IL-1beta on heme metabolism, we determined the delta-aminolevulinic acid synthetase (delta-ALAS) and heme oxygenase activities in the liver. IL-1beta suppressed the microsomal total P450 and heme contents and delta-ALAS activity in the liver. In contrast, microsomal heme oxygenase activity was significantly increased by the IL-1beta treatments. Western blot analysis and marker enzyme activities for individual P450 isoforms demonstrated that IL-1beta suppressed CYP2C6, 2C13, 2E1, and 3A2, whereas CYP2A, 2B1/2, 2C11, and 4A1 were not influenced by the treatments. IL-1beta inhibited both allylisopropylamide- and phenobarbital-inducible delta-ALAS activities in the liver. These results indicate that IL-1beta has differential effects on the constitutive P450, and also on delta-ALAS and heme oxygenase activities in rat liver. Thus, the modulation of hepatic P450 by IL-1beta is complex, and IL-1beta may be involved in the regulation of both apoprotein synthesis for each P450 isoform and the heme pools in the liver.
通过对雄性斯普拉格-道利大鼠进行体内皮下给药研究，探讨了重组人白细胞介素-1β（IL-1β）对肝细胞色素P450（P450）调节的影响。为评估IL-1β对血红素代谢的影响，我们测定了肝脏中δ-氨基乙酰丙酸合成酶（δ-ALAS）和血红素加氧酶的活性。IL-1β抑制了肝脏微粒体总P450、血红素含量及δ-ALAS活性。相反，IL-1β处理显著增加了微粒体血红素加氧酶活性。针对单个P450同工型的蛋白质免疫印迹分析和标记酶活性表明，IL-1β抑制CYP2C6、2C13、2E1和3A2，而CYP2A、2B1/2、2C11和4A1不受该处理的影响。IL-1β抑制了肝脏中烯丙基异丙基酰胺和苯巴比妥诱导的δ-ALAS活性。这些结果表明，IL-1β对组成型P450以及大鼠肝脏中δ-ALAS和血红素加氧酶活性具有不同的影响。因此，IL-1β对肝脏P450的调节是复杂的，IL-1β可能参与了每个P450同工型载脂蛋白合成及肝脏血红素池的调节。
