Graduate Thesis Or Dissertation
 

Dieldrin stimulates biliary excretion of [14 C] benzo[a]pyrene polar metabolites but does not change the metabolite profile in rainbow trout (Oncorhyncus mykiss)

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  • Feeding rainbow trout 0.3-0.4 mg dieldrinlkg/d for 9-12 weeks stimulated the biliary excretion of a subsequent dose of [¹⁴C]dieldrin by 500% and [³H]7,12- dimethylbenz[a]anthracene (DMBA) by 240%. In vitro work demonstrated that this interaction occurred without induction of the cytochrome P450 system, or other hepatocellular proteins involved in metabolism. The present research examined the effects of dieldrin pretreatment on the disposition of the polycyclic aromatic hydrocarbon, benzo[a]pyrene (BaP). The study assessed whether increased biliary excretion of DMBA in dieldrin-fed fish also occurred with BaP, a closely related compound. This substrate, which undergoes complex metabolism, characterized the in vivo state of the cytochrome P450 system, UDP-glucuronyltransferases, and sulfotransferases. Rainbow trout were fed control or dieldrin diets (0.324 mg dieldrinlkgld for 9 weeks or 0.162 mg dieldrinlkg/d for 11 weeks), followed by an ip challenge dose of [¹⁴C]BaP (10 μmols/kg). In experiment 1, dieldrin pretreatment significantly elevated the concentration of [¹⁴C]BaP in bile (142% and 200% at 9 and 12 weeks, respectively) but not liver or fat. In experiment 2, the concentration of ['4C]BaP was elevated in bile (223%), liver (232%), and fat (268%), however, the difference was not significant relative to controls. Extraction of bile sub-samples confinned dieldrin pretreatment significantly stimulated total biliary excretion of [¹⁴C]BaP polar metabolites (244% and 221% at week 9 and 12, respectively in experiment 1; 197% in experiment 2). Bile was extracted and then hydrolyzed by fl-glucuronidase and arylsulfatase to regenerate BaP metabolites conjugated by phase II enzymes. Evaluation of biliary polar metabolite profiles of [¹⁴C]BaP revealed no significant differences between control and dieldrin-fed fish. There was no indication of selective enhancement of any particular peak or induction of a novel biotransformation pathway with dieldrin pretreatment. General increases in many of the biliary metabolite fractions from dieldrin-fed fish were observed, suggesting that a particular P450 was not altered. This study confirmed that enhanced biliary excretion, following chronic dieldrin exposure, is not explained by induction of xenobiotic metabolizing enzymes. The results are consistent with induction of hepatic intracellular trafficking proteins in dieldrin-fed fish.
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