Disposition of 2,3,7,8-tetrabromodibenzo-p-dioxin and 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat: biliary excretion and induction of cytochromes CYP1A1 and CYP1A2.
The biologic activity and pharmacokinetic properties of 2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD) are similar to those of the chlorinated congener, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Metabolism of both compounds appears to be rate-limiting for excretion, which is primarily via the feces. Therefore, the biliary elimination of TBDD and TCDD was examined as an indirect assessment of metabolism. Male F344 rats were anesthetized with pentobarbital, and 1 nmol/kg [3H]TBDD or [3H]TCDD was administered iv. Bile was collected for up to 8 hr while rats were maintained under anesthesia. The rate of biliary excretion of radioactivity was slightly greater for TCDD than TBDD (10% vs 7% in 5 hr). All biliary radioactivity was attributable to metabolites. High pressure liquid chromatographic (HPLC) profiles of biliary radioactivity were similar for [3H]TBDD and [3H]TCDD. To determine if pretreatment altered elimination kinetics, a single dose of 100 nmol/kg TBDD or TCDD was administered to rats by oral gavage 3 days prior to iv injection of 1 nmol/kg [3H]TBDD or [3H]TCDD, respectively. Biliary excretion of the radiolabeled dose was quantitatively and qualitatively unaffected by pretreatment despite a twofold increase in hepatic levels of radiolabel in the pretreated animals. Therefore, under these experimental conditions, autoinduction of TCDD and TBDD metabolism did not occur in the rat in vivo at doses which elicited enhanced hepatic uptake. In a second set of studies, the dose-response profiles for induction of cytochromes CYP1A1 and CYP1A2 by TBDD were characterized. The ED50 value for CYP1A1 induction (measured by ethoxyresorufin O-deethylase activity and radioimmunoassay (RIA) was estimated to be 0.8-1.0 nmol/kg, similar to what has been reported for TCDD. Induction of CYP1A2 (RIA) by TBDD appeared to be a more sensitive response over the dose range studied. Finally, comparison of hepatic CYP1A2 induction vs hepatic concentrations of TBDD 3 days following treatment with 10 vs 1 nmol/kg TBDD suggested that induction of CYP1A2 alone may not account for nonlinearities in dioxin disposition exemplified by dose-related increases in the ratio of dioxin concentrations in liver and adipose tissue.
Kedderis
L B
LB
Curriculum in Toxicology, University of North Carolina, Chapel Hill 27599.
Diliberto
J J
JJ
Linko
P
P
Goldstein
J A
JA
Birnbaum
L S
LS
D000818:Animals; D001659:Biliary Tract / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004147:Dioxins / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D008099:Liver / Q000378:metabolism; D008297:Male; D000072317:Polychlorinated Dibenzodioxins / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344; D013723:Teratogens / Q000493:pharmacokinetics*; D014316:Tritium
D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D013723:Teratogens; C066841:2,3,7,8-tetrabromodibenzo-4-dioxin; D014316:Tritium; D003577:Cytochrome P-450 Enzyme System