Suppression of intestinal and hepatic cytochrome P4503A in murine Toxoplasma infection. Effects of N-acetylcysteine and N-G-monomethyl-L-arginine on the hepatic suppression
Suppression of intestinal and hepatic cytochrome P4503A in murine Toxoplasma infection. Effects of N-acetylcysteine and N-G-monomethyl-L-arginine on the hepatic suppression
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DOI：
10.3109/00498259609046717
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发表时间：
1996-04-01
期刊：
影响因子：
1.8
通讯作者：
Benet, LZ
中科院分区：
文献类型：
--
作者：
BergCandolfi, M;Candolfi, E;Benet, LZ
1. 在小鼠感染模型中研究了细胞色素 P4503A (CYP3A) 的表达。小鼠被弓形虫囊原株感染，并在感染后第10天为肝匀浆和空肠绒毛尖端肠细胞制备微粒体。测定总细胞色素P450（CYP）和CYP3A的含量，并测定CYP3A的活性。 2．在受感染的小鼠中，肝脏（分别为-39％和-49％）和肠道（分别为-43％和-48％）和肠道（分别为-43％和-48％）中CYP和CYP3A总含量下降，CYP3A活性的两种标记物红霉素（fry）和环孢菌素A（CyA）的代谢率也下降（肝脏中为-36％和-26％，肠道中为-35％和-58％）3。为了确定肝脏 CYP3A 抑制的机制，感染小鼠在感染后第 75 天用抗干扰素-γ（抗-IFN-γ）的单克隆抗体进行治疗，或在感染后第 75 天至第 10 天用 N-G-单甲基-L-精氨酸（NMMA）（一种活性氮中间体（RNI）产生的抑制剂）或 N-乙酰半胱氨酸进行治疗(NAC)，一种活性氧中间体(ROI)清除剂。4．用抗-IFN-γ治疗的感染小鼠的肝脏中总CYP含量得到恢复，但存在明显的个体差异。 NAC 治疗导致肝脏总 CYP 含量（+35%）、CYP3A 含量（总恢复）以及 Fry（+59%）和 CyA（+87%）代谢率的恢复，而 NMMA 获得的结果不一致。这些结果表明，NAC（但可能不是 NMMA）可以部分保护小鼠肝脏 CYP3A 免受弓形虫介导的抑制。
1. Cytochrome P4503A (CYP3A) expression was studied in a murine model of infection. Mice were infected with a cystogenic strain of Toxoplasma gondii and microsomes were prepared for liver homogenates and jejunum villus tip enterocytes on day 10 postinfection. Total cytochrome P450 (CYP) and CYP3A were quantitated, and CYP3A activity was determined.2. In the infected mouse, total CYP and CYP3A contents fell in the liver (-39 and -49% respectively) and intestine (-43 and -48% respectively), as did the rate of metabolism of erythromycin (fry) and cyclosporine A (CyA), two markers of CYP3A activity (-36 and -26% in the liver, -35 and -58% in the intestine).3. To determine the mechanism(s) involved in the depression of hepatic CYP3A, infected mice were treated on day 75 post-infection with a monoclonal antibody raised against interferon-gamma (anti-IFN-gamma), or from days 75 to 10 post-infection with either N-G-monomethyl-L-arginine (NMMA), an inhibitor of reactive nitrogen intermediates (RNI) production, or N-acetylcysteine (NAC), a reactive oxygen intermediates (ROI) scavenger.4. Total CYP content was restored in the liver of infected mice treated with anti-IFN-gamma, but with marked interindividuaI variability. NAC treatment led to a recovery in the liver of total CYP content (+35%), CYP3A content (total recovery), and the rates of Fry (+59%) and CyA (+87%) metabolism, whereas inconsistent results were obtained with NMMA. These results suggest that NAC, but probably not NMMA, partially protects hepatic CYP3A from Toxoplasma-mediated suppression in mouse.