Mobilization of vitamin a stores in rats after administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin: A kinetic analysis

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 administ ered TCDD (7.0 mu g/kg b.w,) orally to rats that had received a nonperturbi ng (tracer) iv dose of [H-3]vitamin A-labeled plasma (n = 3) or lymph (n = 3) 21 days earlier. Within a few days after TCDD administration, fraction o f the injected radiolabel in plasma, which had been in a terminal slope whe n plotted on a semilog scale, increased and remained elevated until the exp eriment was terminated (day 42), At that time, liver vitamin A levels were 65% lower in TCDD-perturbed rats than in controls. Using model-based compar tmental analysis and compartmental models developed previously for control rats (S. K. Kelley ef al,, 1998, Toxicol. Sci, 44:1-13), we determined the minimal changes needed to account for the perturbation in plasma [H-3] trac er responses after TCDD administration. We determined that the effects of T CDD could be explained by adjusting the value of one fractional transfer co efficient corresponding to the mobilization of vitamin A from large, slowly turning-over pools. We speculate that this change corresponds to an increa sed fractional rate of retinyl ester hydrolysis, and that it precedes the T CDD-associated increased irreversible utilization and excretion of vitamin A.