TY - JOUR
T1 - Use of model-based compartmental analysis to study effects of 2,3,7,8- tetrachlorodibenzo-p-dioxin on vitamin A kinetics in rats
AU - Kelley, Sean K.
AU - Nilsson, Charlotte B.
AU - Green, Michael H.
AU - Green, Joanne Balmer
AU - Håkansson, Helen
N1 - Funding Information:
1This project was supported by funds from the Swedish Environmental Protection Agency, Visiting Scientist grants from the Karolinska Institute, and a Fulbright Fellowship to S.K.K.
PY - 1998/7
Y1 - 1998/7
N2 - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic, widespread environmental contaminant that has dramatic adverse effects on the metabolism of vitamin A. We used model-based compartmental analysis to investigate sites and quantitative impacts of TCDD on vitamin A kinetics in rats given an oral loading dose of TCDD in oil (3.5 μg/kg) followed by weekly maintenance doses (0.7 μg/kg) or oil only. [3H]Retinol in its plasma transport complex (experiment 1) or lymph containing chylomicrons labeled mainly with [3H]retinyl esters (experiment 2) were administered iv, and tracer kinetics in plasma, liver, carcass, urine, and feces were measured for up to 42 days. TCDD treatment caused significant reductions in liver vitamin A levels and significant changes in tracer kinetics and tracer excretion. A four- compartment model was used to fit tracer data for experiment 1; for experiment 2, compartments were added to describe the metabolism of newly absorbed vitamin A. The compartmental models predict that TCDD caused a slight delay in plasma clearance (via an increased recycling to plasma), and in liver processing, of chylomicron-derived vitamin A. Models for both experiments predict that TCDD exposure did not affect the fractional uptake of plasma retinol from the rapidly turning-over extravascular pool, but it doubled the fractional transfer of recycled retinol from slowly turning-over pools of vitamin A to plasma. The residence time for vitamin A was reduced by 70% in TCDD-treated rats, transfer into urine and feces was tripled, and vitamin A utilization rates were significantly increased. Since our results do not indicate that retinol esterification is inhibited, we hypothesize that some of the significant effects of TCDD on vitamin A metabolism result from increased catabolism and mobilization of vitamin A from slowly turning-over pools (especially the liver).
AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic, widespread environmental contaminant that has dramatic adverse effects on the metabolism of vitamin A. We used model-based compartmental analysis to investigate sites and quantitative impacts of TCDD on vitamin A kinetics in rats given an oral loading dose of TCDD in oil (3.5 μg/kg) followed by weekly maintenance doses (0.7 μg/kg) or oil only. [3H]Retinol in its plasma transport complex (experiment 1) or lymph containing chylomicrons labeled mainly with [3H]retinyl esters (experiment 2) were administered iv, and tracer kinetics in plasma, liver, carcass, urine, and feces were measured for up to 42 days. TCDD treatment caused significant reductions in liver vitamin A levels and significant changes in tracer kinetics and tracer excretion. A four- compartment model was used to fit tracer data for experiment 1; for experiment 2, compartments were added to describe the metabolism of newly absorbed vitamin A. The compartmental models predict that TCDD caused a slight delay in plasma clearance (via an increased recycling to plasma), and in liver processing, of chylomicron-derived vitamin A. Models for both experiments predict that TCDD exposure did not affect the fractional uptake of plasma retinol from the rapidly turning-over extravascular pool, but it doubled the fractional transfer of recycled retinol from slowly turning-over pools of vitamin A to plasma. The residence time for vitamin A was reduced by 70% in TCDD-treated rats, transfer into urine and feces was tripled, and vitamin A utilization rates were significantly increased. Since our results do not indicate that retinol esterification is inhibited, we hypothesize that some of the significant effects of TCDD on vitamin A metabolism result from increased catabolism and mobilization of vitamin A from slowly turning-over pools (especially the liver).
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U2 - 10.1006/toxs.1998.2467
DO - 10.1006/toxs.1998.2467
M3 - Article
C2 - 9720135
AN - SCOPUS:0031846968
SN - 1096-6080
VL - 44
SP - 1
EP - 13
JO - Toxicological Sciences
JF - Toxicological Sciences
IS - 1
ER -