The long-term objectives of this project are to understand the role of the intestine in the initial processing of dietary environmental procarcinogens of the PAH type, the effect of long-term, low level dietary exposure of animals to PAH which induce xenobiotic metabolizing enzymes, and the role of biotransformation, especially sulfation, of hydroxylated PAH in the intestine as a modulator of species differences in susceptibility to the adverse effects of environmental toxicants. This application addresses hypotheses related to the fate of dietary PAH and PAH metabolites in fish species that are anatomically well-suited for studies of intestinal uptake and biotransformation and that serve as models that are reputed to be very sensitive (brown bullhead and winter flounder) or relatively resistant (channel catfish) to PAH-type carcinogens.
The specific aims are: 1) to investigate the dose-dependent and temporal responses of intestinal phase 1 (CYP1A and epoxide hydrolase) and phase 2 [glutathione S-transferase (GST), UDP-glucuronosyltransferase and sulfotransferase (ST)] enzymes to dietary exposure to beta-naphthoflavone or 3-methylcholanthrene; 2) to determine cellular localizations and substrate specificities of the major forms of ST and GST in intestine; and 3) to investigate factors affecting the intestinal bioavailability and biotransformation of 3-hydroxybenzo(a)pyrene, BaP-7,8-dihydrodiol and 6-hydroxymethylBaP. These studies will use radiolabeled BaP metabolites and be conducted at several levels of biological organization including in vitro preparations of intestinal mucosa, in situ studies of intestinal bioavailability and whole animal in vivo studies.
