Hepatic uptake and metabolism of 2,3,7,8-tetrachlorodibenzo-p-dioxin and 2,3,7,8-tetrachlorodibenzofuran.
The pharmacokinetics of TCDD and related compounds is congener, dose, and species specific, with urinary and biliary excretion being dependent on the metabolism of these compounds. Isolated hepatocytes and liver slices in suspension culture and hepatic microsomes were used as in vitro models to assess the hepatic uptake and metabolism of [3H]- and [14C]TCDD and [3H]TCDF (0.01-1.0 microM) in control and induced (5 micrograms TCDD/kg, 3 days earlier) male Sprague-Dawley rats. TCDD pretreatment, with an increase in cytochromes P450 1A1 and 1A2 (CYP1A1, CYP1A2), produced an increase in the hepatic uptake of TCDD, while no increase in the hepatic uptake of TCDF was observed. The results are consistent with CYP1A2 serving as a hepatic binding protein for TCDD but not for TCDF. The rates of metabolism of TCDD and TCDF were directly proportional to their concentrations, indicating that the reaction follows first order kinetics at concentrations from 0.01 to 1.0 microM. Very limited metabolism of TCDD and TCDF was observed in control rat liver (0.45 and 3.2 pmol/hr/g hepatocyte wet wt at 0.1 microM, respectively). TCDD induced its own rate of metabolism about two- to fivefold at 1.0 microM but no induction was observed at 0.01 and 0.1 microM. In contrast, TCDD markedly induced the rate of TCDF metabolism at all substrate concentrations. While the results support the role of rat CYP1A1 in TCDF metabolism, the data suggest that CYP1A1 or CYP1A2 may not metabolize TCDD. These results also support the hypothesis that the more rapid metabolism and excretion of TCDF accounts for the relative resistance of the rat to the acute toxicity of TCDF. Comparative studies in rat and human liver microsomes found that TCDF metabolism exhibited first order kinetics in both species. Furthermore, the rate of TCDF metabolism in human liver microsomes was similar to that of control rat liver microsomes. Together the results suggest that TCDF will be far more persistent in rats, and possibly humans, following exposure at low doses which do not significantly induce cytochrome P450 1A1 and/or 1A2.
Olson
J R
JR
Department of Pharmacology and Therapeutics, University of Buffalo, New York 14214.
McGarrigle
B P
BP
Gigliotti
P J
PJ
Kumar
S
S
McReynolds
J H
JH
D000818:Animals; D001572:Benzofurans / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D001572:Benzofurans; D000072317:Polychlorinated Dibenzodioxins; D003577:Cytochrome P-450 Enzyme System; C014211:2,3,7,8-tetrachlorodibenzofuran