Abstract
Vitamin A (VA) kinetics was studied in rats with marginal VA stores before, during, and after inflammation. Rats received orally [11,12-(3)H(N)]retinol ([(3)H]VA; day 0), and inflammation was induced on day 21 with lipopolysacchride (LPS) for 3 days (n = 5) or recombinant human interleukin-6 (rhIL-6) for 7 days (n = 5). Both the fraction of [(3)H]VA and retinol concentrations in plasma were reduced significantly by LPS or rhIL-6. Compartmental analysis using the Windows version of Simulation, Analysis, and Modeling software was applied to group mean data, and non-steady-state models were developed. After absorption, VA kinetics was described by a three-compartment model that included plasma, kidney/interstitium, and liver/carcass. Four mechanisms decreasing plasma retinol were investigated: increased urinary excretion, increased irreversible loss, increased movement into interstitium, and decreased hepatic mobilization. Modeling demonstrated that a 79% reduction in hepatic mobilization of retinol (from 4.3 to 0.9 nmol/h) by 15 h after LPS best accounted for the observed changes in plasma VA kinetics (sum of squares = 9.05 x 10(-07)). rhIL-6 caused an earlier reduction (75% by 5.6 h). These models predicted a return to control values by 10 days after inflammation. If prolonged, inflammation-induced hyporetinolemia can render hepatic retinol unavailable to extrahepatic tissues, possibly leading to their impaired function, as observed in VA-deficient children with measles infection.
Highlights
Vitamin A (VA) kinetics was studied in rats with marginal VA stores before, during, and after inflammation
We have shown previously that inflammation induced with lipopolysaccharide (LPS) or recombinant human interleukin-6 decreases the availability of retinol binding protein (RBP) and increases the concentrations of hepatic retinol or retinyl esters [9, 11]
In which serial measurements of plasma retinol or urinary RBP have been used to monitor the effect of infection-induced inflammation, have not clearly determined the cause and consequences of hyporetinolemia [31, 32]
Summary
Vitamin A (VA) kinetics was studied in rats with marginal VA stores before, during, and after inflammation. Model-based compartmental analysis indicates a reduced mobilization of hepatic vitamin A during inflammation in rats. Supplementation with large doses of VA (200,000 IU of VA on 2 consecutive days) reduced these children’s morbidity, mortality, and risk of blindness [4] This hyporetinolemia has been well documented and is postulated as mediating measles morbidity and mortality, little is known about the mechanism leading to decreased plasma retinol concentrations or its consequences. A major observation from this type of analysis has been the extensive recycling of VA (i.e., retinol and retinyl esters) before it is irreversibly lost [18] Using these techniques, it was determined that the recycling of VA is affected by VA status (i.e., deficiency vs sufficiency) [19] and by nutritional and chemical stressors, including iron deficiency [20], N-(4-hydroxyphenyl)retinamide treatment [21], and 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure [22]. Our objective was to use mathematical modeling and modelbased compartmental analysis to assess the potential mechanisms responsible for inflammation-induced hyporetinolemia
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