BIOVAILABILITY OF CHLORINATED COMPOUNDS

氯化化合物的生物利用度

• 批准号: 6580390
• 负责人: Margaret Olive James
• 金额: $ 13.16万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6580390
• 关键词: biotransformation; catfish; chemical kinetics; chlorohydrocarbon; environmental exposure; environmental toxicology; enzyme activity; food chain contamination; gastrointestinal toxin absorption; gene expression; hazardous substances; laboratory rat; membrane transport proteins; toxin metabolism

The health effects of Superfund chemicals are critically dependent on the amount of biologically active chemical taken up into animals from environmental sources. The long-term objectives of this project are to understand factors governing the uptake and biotransformation of environmental xenobiotics found in food. While physicochemical properties are known to influence xenobiotic absorption, the extent of biotransformation in the intestine, the presence of other xenobiotics, the composition of the ingested materials and the interactions of the chemical with intestinal transport proteins also influence the amount taken up from ingested material. P-glycoprotein (pgp), a plasma membrane bound efflux transporter, is thought to act as a modulating barrier to systemic bioavailability of certain orally administered xenobiotics. Transport by this system is susceptible to induction and inhibition effects. In the catfish GI tract, the Superfund chemicals benzo(a)pyrene (BaP), 3,3',4,4'- tetrachlorobiphenyl (TCB) and some BaP and TCB metabolites were shown to affect intestinal pgp expression and function, and may serve as substrates for the transporter. To further our understanding of factors affecting the systemic bioavailability of toxicants encountered in the diet, and the effect of toxicant exposure on the bioavailability of orally administered therapeutic drugs, this project will focus on the roles of the pgp transporter and biotransformation enzymes (CYP and phase 2 enzymes) in the intestine. The Superfund chemicals TCB, BaP and methoxychlor (MHC) and the model compound nonylphenol ethoxylate (NPE), will be investigated. The effects of exposure to these chemicals on the absorption of two drug substrates for pgp, cyclosporine and tetracycline, will be investigated. The specific aims are as follows. 1. To test the hypothesis that pgp expression and function in intestine, and the expression and activity are drug metabolizing enzymes will be altered by exposure to varying doses of TCB, BaP, MCH and NPE. 2. To test the hypothesis that induction and inhibition of pgp will affect the systemic bioavailability of intestinally administered Superfund chemical and therapeutic drugs that are pgp substrates, especially at low exposure or dose levels. 3. To test the hypothesis that intestine contributes to the biotransformation of dietary Superfund chemicals and their primary metabolites. 4. To test the hypothesis that in the absence of significant biotransformation, transporter function will be a major determinant of the bio-accumulation of low levels of Superfund chemicals that are pgp substrates. These studies will be conducted in vitro, in situ and in vivo with channel catfish and rat as the model animal species, and will utilize radiolabeled chemicals for some studies.

超级基金化学品对健康的影响严重依赖于从环境来源摄入动物体内的生物活性化学物质的数量。该项目的长期目标是了解控制食品中发现的环境异生物质的吸收和生物转化的因素。虽然已知物理化学性质会影响异物的吸收，但肠道中生物转化的程度、其他异物的存在、摄取物质的组成以及化学物质与肠道运输蛋白的相互作用也会影响摄取物质的量。P-糖蛋白(Pgp)是一种质膜结合的外排转运蛋白，被认为是某些口服外源药物系统生物利用度的调节屏障。这种系统的运输容易受到诱导和抑制作用的影响。在鲶鱼GI区，Superfund化学物质苯并(A)芘(BaP)、3，3‘，4，4’-四氯联苯(TCB)以及一些BaP和TCB代谢产物可以影响肠道Pgp的表达和功能，并可能作为转运蛋白的底物。为了进一步了解影响饮食中毒物系统生物利用度的因素，以及毒物暴露对口服治疗药物生物利用度的影响，本项目将重点研究PGP转运体和生物转化酶(CYP和2相酶)在肠道中的作用。超级基金化学品TCB、BaP和甲氧氯胺(MHC)以及模型化合物壬基酚聚氧乙烯醚(NPE)将被调查。我们将研究接触这些化学物质对PGP的两种药物基质--环孢素和四环素吸收的影响。具体目标如下。1.通过不同剂量的TCB、BaP、MCH和NPE的作用，验证Pgp在肠道中的表达和功能，以及Pgp的表达和活性是药物代谢酶的假说。2.验证PGP的诱导和抑制将影响作为PGP底物的Superfund化疗药物和治疗药物在肠道内的系统生物利用度的假设，特别是在低暴露或低剂量水平下。3.检验肠道对饲料中Superfund化学物质及其主要代谢物的生物转化的贡献。4.检验假设，即在没有显著的生物转化的情况下，转运蛋白功能将是作为PGP底物的低水平超级基金化学物质生物积累的主要决定因素。这些研究将以斑点叉尾鱼和大鼠为模式动物物种，在体外、原位和体内进行，并将利用放射性标记的化学物质进行一些研究。