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

• Published in: Toxicological sciences Vol. 55; no. 2; pp. 478 - 484
• Main Authors: KELLEY, S. K, NILSSON, C. B, GREEN, M. H, GREEN, J. B, HAKANSSON, H
• Format: Journal Article
• Language: English
• Published: Cary, NC Oxford University Press 01-06-2000
• Subjects: Administration, Oral; Animals; Animals, Newborn; Biological and medical sciences; Body Weight - drug effects; Chemical and industrial products toxicology. Toxic occupational diseases; Environmental Pollutants - toxicity; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Medical sciences; Medicin och hälsovetenskap; Models, Biological; Organ Size - drug effects; Polychlorinated Dibenzodioxins - toxicity; Rats; Rats, Sprague-Dawley; Thymus Gland - drug effects; Thymus Gland - pathology; Toxicology; Various organic compounds; Vitamin A - pharmacokinetics; Rat; Rodentia; Vitamin; Oxygen heterocycle; Ingestion; Retinol; Toxicokinetics; Vertebrata; Compartmental model; Mammalia; Animal; Chlorine Organic compounds; Aromatic compound; Kinetics
• ISSN: 1096-6080; 1096-0929; 1096-0929
• DOI: 10.1093/toxsci/55.2.478

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.