Bleau A M, Levitchi M C, Maurice H, du Souich P
Department of Pharmacology, Faculty of Medicine, University of Montréal, Montréal, Québec, Canada.
Br J Pharmacol. 2000 Aug;130(8):1777-84. doi: 10.1038/sj.bjp.0703486.
Serum from humans with an acute upper respiratory viral infection and from rabbits with turpentine-induced inflammation reduce the catalytic activity of hepatic cytochrome P450 (P450). The aim of this study was to identify the serum mediators responsible for the decrease in P450 activity. Rabbit and human sera were fractionated by size exclusion chromatography and the fractions tested for their ability to reduce the activity and amount of P450 after 4 h of incubation with hepatocytes from turpentine-treated rabbits (H(INF)). Rabbit and human sera decreased P450 activity by around 40% without any change in the amount of CYP1A1 and 1A2 apoproteins. In rabbit serum, the fraction containing proteins of M(r) 23-15 kDa decreased P450 content by 41%, but did not alter the amount of the apoproteins. Anti-IL-6 antibody added to the M(r) 23-15 kDa fraction restored P450 content to 97% of control values, while anti-IL-1beta, TNF-alpha and IFN-gamma antibodies had no effect. Supporting the role of IL-6, incubation of H(INF) in the presence of IL-6 for 4 h reduced P450 content by 40%. In human serum, the fraction containing proteins of M(r) >95 kDa lowered P450 content by 43% without modifying the amounts of CYP1A1/2. Neutralization experiments showed that IFN-gamma, IL-6, and IL-1beta contributed to the decrease in P450 content. In conclusion, the present results demonstrate that IL-6, and IFN-gamma, IL-6 and IL-1beta are the serum mediators released in vivo by a turpentine-induced inflammatory reaction in the rabbit and an upper respiratory viral infection in humans, respectively, inactivating hepatic P450.
患有急性上呼吸道病毒感染的人类血清以及经松节油诱导产生炎症的兔子血清，均可降低肝细胞色素P450（P450）的催化活性。本研究的目的是确定导致P450活性降低的血清介质。通过尺寸排阻色谱法对兔子和人类血清进行分级分离，并检测各分级部分在与经松节油处理的兔子的肝细胞（H(INF)）孵育4小时后降低P450活性和含量的能力。兔子和人类血清使P450活性降低约40%，而CYP1A1和1A2载脂蛋白的量没有任何变化。在兔子血清中，含有分子量为23 - 15 kDa蛋白质的分级部分使P450含量降低了41%，但未改变载脂蛋白的量。添加到分子量为23 - 15 kDa分级部分的抗IL - 6抗体使P450含量恢复到对照值的97%，而抗IL - 1β、TNF - α和IFN - γ抗体则没有作用。支持IL - 6的作用的是，在IL - 6存在的情况下将H(INF)孵育4小时可使P450含量降低40%。在人类血清中，含有分子量>95 kDa蛋白质的分级部分使P450含量降低了43%，而未改变CYP1A1/2的量。中和实验表明，IFN - γ、IL - 6和IL - 1β促成了P450含量的降低。总之，目前的结果表明，IL - 6以及IFN - γ、IL - 6和IL - 1β分别是兔子体内松节油诱导的炎症反应和人类上呼吸道病毒感染在体内释放的血清介质，可使肝脏P450失活。
