Toxicological Sciences 55, 478-484 (2000)
Copyright © 2000 by the Society of Toxicology
Mobilization of Vitamin A Stores in Rats after Administration of 2,3,7,8-Tetrachlorodibenzo-p-dioxin: A Kinetic Analysis
,1
* The Institute of Environmental Medicine, Karolinska Institutet, P.O. Box 210, S-177 77 Stockholm, Sweden; and
Graduate Program in Physiology and Nutrition Department, Pennsylvania State University, University Park, Pennsylvania 16802
Part of this work was presented in the doctoral theses of Sean Keith Kelley ("The Effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin on Vitamin A Kinetics in Rats: A Compartmental Model," Pennsylvania State University, University Park, PA, 1997) and Charlotte B. Nilsson ("Studies on the Effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin on Vitamin A Homeostasis," Karolinska Institutet, Stockholm, Sweden, 1999).
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic environmental contaminant that prevents the normal accumulation of vitamin A in liver and causes increased excretion of vitamin A. To determine what alterations in vitamin A metabolism occur first in response to TCDD treatment, we administered TCDD (7.0 µg/kg b.w.) orally to rats that had received a nonperturbing (tracer) iv dose of [3H]vitamin A-labeled plasma (n = 3) or lymph (n = 3) 21 days earlier. Within a few days after TCDD administration, fraction of the injected radiolabel in plasma, which had been in a terminal slope when plotted on a semilog scale, increased and remained elevated until the experiment was terminated (day 42). At that time, liver vitamin A levels were 65% lower in TCDD-perturbed rats than in controls. Using model-based compartmental analysis and compartmental models developed previously for control rats (S. K. Kelley et al., 1998, Toxicol. Sci, 44:1–13), we determined the minimal changes needed to account for the perturbation in plasma [3H] tracer responses after TCDD administration. We determined that the effects of TCDD could be explained by adjusting the value of one fractional transfer coefficient corresponding to the mobilization of vitamin A from large, slowly turning-over pools. We speculate that this change corresponds to an increased fractional rate of retinyl ester hydrolysis, and that it precedes the TCDD-associated increased irreversible utilization and excretion of vitamin A.
Key Words: 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD; rat; vitamin A; model-based compartmental analysis; kinetics.
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