Bleau A M, Fradette C, El-Kadi A O, Côté M C, du Souich P
Department of Pharmacology, Faculty of Medicine, University of Montréal, Montréal, Québec, Canada.
Drug Metab Dispos. 2001 Jul;29(7):1007-12.
Serum from humans with an upper respiratory viral infection (HS(URVI)) and from rabbits with a turpentine-induced acute inflammatory reaction (RS(TIAR)) reduces the activity of hepatic cytochrome P450 (P450) following 4 h of incubation. The aim of the present study was to assess the effect of HS(URVI) and RS(TIAR) on P450 activity and expression following 24 h of incubation with hepatocytes from control (H(CONT)) and rabbits with a TIAR (H(INFLA)). RS(TIAR) incubated with H(CONT) for 24 h reduced P450 content and activity, and CYP3A6 by 45%, without changing CYP1A1 and 1A2; when incubated with H(INFLA), RS(TIAR) decreased P450 content and activity without affecting CYP1A1 or 1A2. HS(URVI) incubated for 4 h with H(CONT) decreased P450 activity without affecting the amounts of CYP1A1, 1A2, or 3A6, although when incubated for 24 h, P450 activity and CYP3A6 amount decreased. HS(URVI) incubated with H(INFLA) for 4 h reduced P450 content and activity, and incubated for 24 h reduced activity, P450 content, and amount of CYP1A1 and 1A2 proteins. The present study demonstrates that 1) the effect of RS(TIAR) and HS(URVI) depends upon the susceptibility of the hepatocyte, i.e., H(CONT) or primed H(INFLA); 2) P450 down-regulation is preceded by a decrease in P450 activity; 3) the nature of the inflammatory reaction determines the repercussions on P450 activity and expression; and 4) CYP3A6 is more vulnerable than CYP1A1 and 1A2 to the down-regulation provoked by an inflammatory challenge.
来自上呼吸道病毒感染患者（HS(URVI)）的血清以及来自用松节油诱导产生急性炎症反应的兔子（RS(TIAR)）的血清，在孵育4小时后会降低肝细胞色素P450（P450）的活性。本研究的目的是评估HS(URVI)和RS(TIAR)在与对照肝细胞（H(CONT)）以及患有松节油诱导的急性炎症反应的兔子的肝细胞（H(INFLA)）孵育24小时后对P450活性和表达的影响。RS(TIAR)与H(CONT)孵育24小时会降低P450含量和活性，使CYP3A6降低45%，而CYP1A1和1A2不变；与H(INFLA)孵育时，RS(TIAR)会降低P450含量和活性，但不影响CYP1A1或1A2。HS(URVI)与H(CONT)孵育4小时会降低P450活性，但不影响CYP1A1、1A2或3A6的量，不过孵育24小时后，P450活性和CYP3A6的量会降低。HS(URVI)与H(INFLA)孵育4小时会降低P450含量和活性，孵育24小时会降低活性、P450含量以及CYP1A1和1A2蛋白的量。本研究表明：1）RS(TIAR)和HS(URVI)的作用取决于肝细胞的易感性，即H(CONT)或预处理过的H(INFLA)；2）P450下调之前P450活性会降低；3）炎症反应的性质决定了对P450活性和表达的影响；4）CYP3A6比CYP1A1和1A2更容易受到炎症刺激引起的下调作用的影响。
