Garcia Del Busto Cano Elena, Renton Kenneth W
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia B3H 4H7, Canada.
J Pharm Sci. 2003 Sep;92(9):1860-8. doi: 10.1002/jps.10433.
Hepatic cytochrome P450 enzymes can be modulated during systemic infections. Inflammatory responses in the brain have also been shown to cause a significant decrease in the levels and activities of important cytochrome P450 isoforms in the liver. We determined some of the effects of central nervous system (CNS) Listeria monocytogenes infection on hepatic cytochrome P450 systems in rats. Intracerebroventricular injection of L. monocytogenes resulted in a time-dependent modulation of CYP1A, CYP2B, and CYP3A activities in the liver. Total hepatic cytochrome P450 content was significantly lowered 48 h after administration of the bacterium, and hepatic CYP1A and CYP2B activities were significantly altered 48 and 72 h after infection, respectively, whereas CYP3A activity and protein content were depressed 72 h after the insult. Bacterial load in the brain increased dramatically over a 72-h period, but the number of bacteria cultured from liver over this time period was relatively small. Therefore, an infection largely confined to the CNS in the rat results in abnormal activity levels of certain hepatic cytochrome P450 enzymes crucial in drug metabolism. If such a response also occurs in humans, this has the potential to produce serious complications with drug and endogenous substrate metabolism in patients with an infectious disease involving the CNS.
在全身感染期间，肝脏细胞色素P450酶可被调节。脑内的炎症反应也已被证明会导致肝脏中重要细胞色素P450同工酶的水平和活性显著降低。我们确定了中枢神经系统（CNS）单核细胞增生李斯特菌感染对大鼠肝脏细胞色素P450系统的一些影响。脑室内注射单核细胞增生李斯特菌导致肝脏中CYP1A、CYP2B和CYP3A活性出现时间依赖性调节。在注射细菌后48小时，肝脏细胞色素P450的总含量显著降低，感染后48小时和72小时，肝脏CYP1A和CYP2B活性分别显著改变，而CYP3A活性和蛋白含量在损伤后72小时降低。在72小时内，脑内细菌载量急剧增加，但在此期间从肝脏培养出的细菌数量相对较少。因此，大鼠中主要局限于中枢神经系统的感染会导致某些对药物代谢至关重要的肝脏细胞色素P450酶的活性水平异常。如果人类也发生这种反应，那么对于患有涉及中枢神经系统的传染病的患者，这有可能在药物和内源性底物代谢方面产生严重并发症。
