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 administered TCDD (7.0 microg/kg b.w. ) orally to rats that had received a nonperturbing (tracer) iv dose of [(3)H]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 [(3)H] 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.
Kelley
S K
SK
The Institute of Environmental Medicine, Karolinska Institutet, P.O. Box 210, S-177 77 Stockholm, Sweden.
Nilsson
C B
CB
Green
M H
MH
Green
J B
JB
Håkansson
H
H
D000284:Administration, Oral; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D004785:Environmental Pollutants / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008954:Models, Biological; D009929:Organ Size / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology; D014801:Vitamin A / Q000493:pharmacokinetics*
D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D014801:Vitamin A