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.
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