Compartmental modeling of whole-body vitamin A kinetics in unsupplemented and vitamin A-retinoic acid-supplemented neonatal rats

Libo Tan,Amanda E Wray,Michael H Green,A Catharine Ross

doi:10.1194/jlr.m050518

Abstract

Little is known about the contribution of different tissues to whole-body vitamin A (VA) kinetics in neonates. Here, we have used model-based compartmental analysis of tissue tracer kinetic data from unsupplemented (control) and VA-retinoic acid (VARA)-supplemented neonatal rats to determine VA kinetics in specific tissues under control and supplemented conditions. First, compartmental models for retinol kinetics were developed for individual tissues, and then an integrated compartmental model incorporating all tissues was developed for both groups. The models predicted that 52% of chylomicron (CM) retinyl ester was cleared by liver in control pups versus 22% in VARA-treated pups, whereas about 51% of VA was predicted to be extrahepatic in 4- to 6-day-old unsupplemented neonatal rats. VARA increased CM retinyl ester uptake by lung, carcass, and intestine; decreased the release into plasma of retinol that had been cleared by liver and lung as CM retinyl esters; stimulated the uptake of retinol from plasma holo-retinol binding protein into carcass; and decreased the retinol turnover out of the liver. Overall, neonatal VA trafficking differed from that previously described for adult animals, with a larger contribution of extrahepatic tissues to CM clearance, especially after VA supplementation, and a significant amount of VA distributed in extrahepatic tissues.

Highlights

Little is known about the contribution of different tissues to whole-body vitamin A (VA) kinetics in neonates
We utilized [3H]retinol as a tracer for two treatments, an oil treatment in which we determined VA kinetics in unsupplemented neonates and a VA-retinoic acid (VARA) treatment in which the neonates received VA, given at a dose that resembles, adjusted for body weight, the amount of VA given to young infants in VA supplementation studies [6]
Building on the plasma view models recently proposed [5], in the present study we have developed compartmental models for individual tissues, including liver, lung, stomach, intestine, kidney, and the remaining carcass, and an integrated model for control and VARA-treated neonatal rats that incorporates all of these tissues

Summary

Introduction

Little is known about the contribution of different tissues to whole-body vitamin A (VA) kinetics in neonates. We utilized [3H]retinol as a tracer for two treatments, an oil (control placebo) treatment in which we determined VA kinetics in unsupplemented neonates and a VA-retinoic acid (VARA) treatment in which the neonates received VA, given at a dose that resembles, adjusted for body weight, the amount of VA given to young infants in VA supplementation studies [6]. This dose was admixed with one-tenth the amount of RA, a combination we have shown previously to promote retinol uptake into lung tissue [7, 8]. VARA supplementation decreased the recycling number for retinol between plasma and tissues and the time that retinol spends in plasma; it stimulated the uptake of plasma VA into extravascular tissues [5]

Methods

Results

Conclusion