Zhang Q Y, Wikoff J, Dunbar D, Fasco M, Kaminsky L
New York State Department of Health, Wadsworth Center, Albany 12201-0509, USA.
Drug Metab Dispos. 1997 Jan;25(1):21-6.
The predominant inducible cytochrome P450 (CYP) in rat small intestine is CYP1A1, which, when induced to elevated levels by xenobiotics or dietary constituents, has the potential to metabolize and consequently reduce the systemic uptake of low concentrations of orally ingested, bioactivatable polycyclic aromatic hydrocarbons and heterocyclic aromatic amines. We investigated the regulation of small intestinal CYP1A1 in an effort to develop its anticancer potential. The time courses of hepatic and intestinal CYP1A1 induction by beta-naphthoflavone (BNF) were compared quantitatively at the protein and mRNA levels by immunoblot and competitive RNA-polymerase chain reaction analyses. CYP1A1 mRNA levels in both organs increased sharply and were maximal at approximately 6 hr and returned to near basal levels by 12 hr after BNF treatment. In contrast, hepatic CYP1A2 mRNA levels increased much more gradually. Small intestinal CYP1A2 mRNA concentrations were insufficient to support translation of detectable protein. Maximal levels of intestinal and hepatic CYP1A1 protein occurred between 12 and 24 hr, and 24 and 48 hr, respectively, after BNF. Intestinal CYP1A1 protein was detectable earlier and for a shorter duration than hepatic CYP1A1. CYP1A1 induction was first detected in crypt cells 3 hr before the appearance of activity in villous cells, and maximal levels of activity were reached in crypt cells 12 to 18 hr before maximal and 1.5-fold (per mg protein) higher responses in villous cells-induction thus occurs in both villous and crypt cells. Previously detected decreases in CYP1A1 inducibility from duodenum to ileum correlated with decreases in immunoblot determined-Ah receptor levels. Intestinal CYP1A1 induction does not involve the glucocorticoid receptor in contrast to hepatic induction. These studies have revealed several novel features of small intestinal CYP1A1 regulation.
大鼠小肠中主要的可诱导细胞色素P450（CYP）是CYP1A1，当被异生素或饮食成分诱导至高水平时，它有可能代谢并因此降低口服摄入的低浓度可生物活化多环芳烃和杂环芳香胺的全身吸收。我们研究了小肠CYP1A1的调节，以开发其抗癌潜力。通过免疫印迹和竞争性RNA聚合酶链反应分析，在蛋白质和mRNA水平上定量比较了β-萘黄酮（BNF）对肝脏和小肠CYP1A1的诱导时间进程。BNF处理后，两个器官中的CYP1A1 mRNA水平均急剧增加，在约6小时时达到最大值，并在12小时后恢复到接近基础水平。相比之下，肝脏CYP1A2 mRNA水平升高更为缓慢。小肠CYP1A2 mRNA浓度不足以支持可检测蛋白质的翻译。BNF处理后，小肠和肝脏CYP1A1蛋白的最大水平分别出现在12至24小时和24至48小时之间。小肠CYP1A1蛋白比肝脏CYP1A1更早被检测到且持续时间更短。在绒毛细胞出现活性前3小时，在隐窝细胞中首次检测到CYP1A1诱导，在绒毛细胞达到最大活性水平前12至18小时，隐窝细胞中达到最大活性水平，且隐窝细胞中的反应比绒毛细胞高1.5倍（每毫克蛋白质），因此在绒毛和隐窝细胞中均发生诱导。先前检测到的从十二指肠到回肠CYP1A1诱导性的降低与免疫印迹测定的芳烃受体水平的降低相关。与肝脏诱导不同，小肠CYP1A1诱导不涉及糖皮质激素受体。这些研究揭示了小肠CYP1A1调节的几个新特征。
