BIOVAILABILITY OF CHLORINATED COMPOUNDS

超级基金化学品对健康的影响在很大程度上取决于动物从环境来源吸收的生物活性化学品的数量。该项目的长期目标是了解控制食物中发现的环境异种素的吸收和生物转化的因素。虽然已知物化性质会影响外来生物的吸收，但肠道内生物转化的程度、其他外来生物的存在、摄入物质的组成以及化学物质与肠道转运蛋白的相互作用也会影响从摄入物质中吸收的量。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性药物的系统生物利用度的调节屏障。该系统的运输易受诱导和抑制作用的影响。在鲶鱼胃肠道中，超级基金化学物质苯并(a)芘（BaP）， 3,3',4,4'-四氯联苯（TCB）和一些BaP和TCB代谢物被证明影响肠道pgp的表达和功能，并可能作为转运体的底物。为了进一步了解影响饮食中毒性物质的全身生物利用度的因素，以及毒性物质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转运体和肠道生物转化酶（CYP和2期酶）的作用。超级基金化学品TCB， BaP和甲氧基氯（MHC）和模型化合物壬基酚聚氧乙酸酯（NPE），将进行研究。将研究暴露于这些化学物质对pgp的两种药物底物环孢素和四环素的吸收的影响。具体目的如下。1. 为了验证pgp在肠道中的表达和功能以及药物代谢酶的表达和活性会因暴露于不同剂量的TCB、BaP、MCH和NPE而发生改变的假设。2. 为了验证pgp的诱导和抑制会影响肠道给药的以pgp为底物的Superfund化学和治疗药物的全身生物利用度的假设，特别是在低暴露或低剂量水平下。3. 为了验证肠道对膳食超级基金化学物质及其初级代谢物的生物转化有贡献的假设。4. 为了验证这一假设，即在没有显著生物转化的情况下，转运体功能将是低水平超级基金化学物质（pgp底物）生物积累的主要决定因素。这些研究将以通道鲶鱼和大鼠为模型动物进行体外、原位和体内研究，并将在一些研究中使用放射性标记的化学物质。

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.