Date of Award

2000

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical and Veterinary Medical Sciences - Comparative Biomedical Sciences

First Advisor

Kevin M. Kleinow

Abstract

These studies examined the role of micelle fatty acid composition, contaminant body burden, biotransformation, and non-specific toxicity on the systemic bioavailability of 3,4,3',4'-tetrachlorobiphenyl (TCB) from the intestine of catfish, as well as the effect of TCB upon the vectorial transporter p-glycoprotein (pgp). Initial in vitro experiments demonstrated that the solubility of [14C]-TCB in micelles was favored by longer chain fatty acids, with higher [14C]-TCB solubility correlating to greater systemic bioavailability of [14C]-TCB in an in situ preparation. The systemic bioavailability of [14C]-TCB was demonstrated to be affected by in vivo exposures to TCB, in a dose-independent manner, and apparently unrelated to P4501A-related induction or [14C]-TCB metabolism. The latter was detectable, but quantitatively a minor event. Bioavailability decreases in TCB-treated animals resulted from combination of lowered [14C]-TCB transport to the blood, and retention in the lumen which was consistent with permeability changes resulting from toxicity, or most likely, alterations in [14C]-TCB gradients resulting from unlabeled TCB accumulation in the tissues. Dietary pretreatment with the prototypic CYP1A inducer beta-naphthoflavone (BNF) confirmed the lack of effect of intestinal AHH activity induction on the systemic bioavailability of [14C]-TCB. Histological alterations seen with BNF exposures, indistinguishable from those seen with TCB, did not appear to influence [14C]-TCB bioavailability. These latter findings reinforced the assumptions that the effect of TCB preexposure on the subsequent bioavailability of [14C]-TCB is diffusion-related. The pgp-related transporter identified in the catfish intestine was not inducible by dietary exposures to the P4501 A inducers TCB, BNF, benzo(a)pyrene, or the pgp inducer vincristine, under the conditions examined. In addition, functional analysis demonstrated that catfish pgp may exhibit some classic MDR transport abilities. These studies suggest that TCB intestinal biovailability can be modulated by micelle fatty acid composition, as well as TCB exposure history. First-pass intestinal metabolism appears to be an evident, but minor event in the biotransformation of dietary TCB. Furthermore, studies with catfish pgp suggested that induction of CYP1A and pgp appear to be unrelated events in the catfish intestine.

ISBN

9780599905863

Pages

173

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