Cashman John R, Lattard Virginie, Lin Jing
Human BioMolecular Research Institute, San Diego, CA 92121, USA.
Drug Metab Dispos. 2004 Feb;32(2):222-9. doi: 10.1124/dmd.32.2.222.
Total parenteral nutrition provides nutrition by infusion into the systemic circulation. Bypassing the intestine and processes associated with absorption can cause additional pathophysiological changes to occur. For example, in rats, normal gut and pancreatic cell function may change, absorptive capacity may be altered, and enzyme functional activity including drug metabolism may be affected. The objective of this study was to examine the effects of a control diet or a diet of total parenteral nutrition in the presence or absence of choline on urinary biomarkers and hepatic microsome functional activity from rats. Selective functional markers of cytochrome P-4502E1 (CYP2E1) and flavin-containing monooxygenase (FMO) were examined in vitro. The N-oxygenation of trimethylamine was used as an in vivo selective functional marker for FMO. After the administration of total parenteral nutrition plus choline for 5 days, the urinary excretion of trimethylamine and trimethylamine N-oxide declined approximately 7- and 3-fold, respectively, compared with rats treated with control diet. The concentration of urinary biogenic amines was also significantly affected by total parenteral nutrition. Compared with control animals, rats administered total parenteral nutrition plus choline for 5 days showed a decrease of approximately 5- and 2-fold in urinary dopamine and norepinephrine concentration, respectively. To examine a molecular basis for the influence of total parenteral nutrition +/- choline on monooxygenase regulation, hepatic microsomal activity of the FMO and CYP2E1 was examined. Compared with animals treated with a control diet, total parenteral nutrition plus choline in rats caused a 3-fold increase in hepatic microsomal FMO and a 2-fold increase in hepatic cytochrome CYP2E1 functional activity, respectively. Although the data did not reach statistical significance, selective immunoblot studies using hepatic microsomes from rats treated with total parenteral nutrition + choline showed that compared with controls, FMO1 protein was decreased 1.4-fold and FMO3 increased 1.3-fold, respectively. In hepatic microsomes from rats treated with total parenteral nutrition + choline, compared with control animals, FMO4 immunoreactivity was increased 1.6-fold. The data suggest that total parenteral nutrition has a detectable effect on modulating rat FMO3, FMO4, and CYP2E1 monooxygenase functional activity. The clinical relevance of these results is unknown but may be of significance for individuals receiving total parenteral nutrition and those afflicted with trimethylaminuria.
全胃肠外营养通过输注到体循环中来提供营养。绕过肠道及与吸收相关的过程会导致额外的病理生理变化发生。例如，在大鼠中，正常的肠道和胰腺细胞功能可能会改变，吸收能力可能会改变，包括药物代谢在内的酶功能活性可能会受到影响。本研究的目的是研究在有或没有胆碱的情况下，对照饮食或全胃肠外营养饮食对大鼠尿液生物标志物和肝微粒体功能活性的影响。在体外检测了细胞色素P-4502E1（CYP2E1）和含黄素单加氧酶（FMO）的选择性功能标志物。三甲胺的N-氧化用作FMO的体内选择性功能标志物。给予全胃肠外营养加胆碱5天后，与给予对照饮食的大鼠相比，三甲胺和三甲胺N-氧化物的尿排泄量分别下降了约7倍和3倍。全胃肠外营养也显著影响尿液生物胺的浓度。与对照动物相比，给予全胃肠外营养加胆碱5天的大鼠尿多巴胺和去甲肾上腺素浓度分别下降了约5倍和2倍。为了研究全胃肠外营养±胆碱对单加氧酶调节影响的分子基础，检测了FMO和CYP2E1的肝微粒体活性。与给予对照饮食的动物相比，给予全胃肠外营养加胆碱的大鼠肝微粒体FMO增加了3倍，肝细胞色素CYP2E1功能活性增加了2倍。虽然数据未达到统计学显著性，但使用给予全胃肠外营养加胆碱的大鼠肝微粒体进行的选择性免疫印迹研究表明，与对照组相比，FMO1蛋白分别减少了1.4倍，FMO3增加了1.3倍。在给予全胃肠外营养加胆碱的大鼠肝微粒体中，与对照动物相比，FMO4免疫反应性增加了1.6倍。数据表明全胃肠外营养对调节大鼠FMO3、FMO4和CYP2E1单加氧酶功能活性有可检测到的影响。这些结果的临床相关性尚不清楚，但可能对接受全胃肠外营养的个体和患有三甲胺尿症的人具有重要意义。
