Vitamin A and Retinoic Acid Combined Have a More Potent Effect Compared with Vitamin A Alone on the Uptake of Retinol into Extrahepatic Tissues of Neonatal Rats Raised under Vitamin A–Marginal Conditions

Abstract

Background Vitamin A (VA, retinol) supplementation is widely used to reduce child mortality in low-income countries. However, existing research suggests that supplementation with VA alone may not be optimal for infants. Objective We compared the effect of VA vs. VA combined with retinoic acid (VARA) on retinol uptake and turnover in organs of neonatal rats raised under VA-marginal conditions. Methods Secondary analysis was conducted on data obtained from two prior kinetic studies of Sprague-Dawley neonatal rats nursed by mothers fed a VA-marginal diet (0.35 mg retinol equivalents/kg diet). On postnatal d 4, pups had been treated with a single dose of VA (6 μg/g; n = 52; VA study), VA + 10% retinoic acid (6 μg/g; n = 42; VARA study) or placebo (canola oil; n = 94; both studies), all containing ~2 μCi of [3H]retinol as the tracer for VA. Total retinol concentrations and tracer levels had been measured in plasma and tissues from 1 h to 14 d after dosing. Control group data from both studies were merged prior to analysis. Kinetic parameters were re-estimated and compared statistically. Results VARA supplementation administered to neonatal rats within a few days after birth resulted in a lower turnover of retinol in the lungs, kidneys, and carcass and less frequent recycling of retinol between plasma and organs (100 vs. 288 times in VARA- vs. VA-treated group). Although the VA supplementation resulted in a higher concentration of retinol in the liver, VARA supplementation led to a higher uptake of postprandial retinyl esters into the lungs, intestines, and carcass. Conclusions Given the relatively higher retinol uptake into several extrahepatic organs of neonates dosed orally with VARA, this form of supplementation may serve as a targeted treatment of low VA levels in the extrahepatic organs that continue to develop postnatally.

Metabolism of Neonatal Vitamin A Supplementation: A Systematic Review

“…Calves given a large dose on day 3 and day 10 of life had higher serum VA than controls on 10 and 20 d of life ( 85 ). Rats given single ( 80 , 81 ) or multiple ( 86 ) high doses of VA did not have different plasma VA concentrations than controls by 15 h or 2 d postdosing, respectively. Control rats had higher total plasma retinol mass at 14 d but no other times before or after; total retinol concentration and retinyl ester concentration was similar between groups at 2–24 d ( 80 ).…”

“…Long-term concentrations of VA in organs were assessed in calf studies as well as more recent studies in rats and swine ( Table 3 ). Liver VA was maintained at higher concentrations in dosed animals than controls at 7–11 d postdose in calves ( 74 , 85 ), through to 11 and 14 d in rats ( 80 , 81 ), and showed a dose response from 24 h through to 10 d postdose in piglets ( 58 , 76 ). Furthermore, piglet liver storage was also dependent on the mother's VA status, with more of the dose stored in piglets from less deficient mothers; however, sow milk VA concentration did not differ between sow groups of differing VA status ( 58 ).…”

“…Rats receiving NVAS on postnatal days 5–7 had higher plasma retinol than controls 24 h after the last dose: (∼1.55 compared with ∼1.05 μmol/L, respectively, P < 0.05) ( 78 ) and (1.8 compared with 1.4 μmol/L, respectively, no statistics reported) ( 79 ). Rats dosed on postnatal day 4 had elevated serum retinol and retinyl ester concentrations compared with controls peaking at 1 h and returning to control concentrations by 8–15 h after dosing, with the increase primarily representing retinyl esters associated with chylomicra ( 80 , 81 ). Full-term human neonates tended to have a higher serum retinol response than prematurely born neonates ( 69 ), and aqueous preparations (solubilized in propylene glycol, glycerin, or another dispersing agent) had a significantly higher serum retinol response than the oily preparation ( 68 , 70 , 71 ).…”

“…Following NVAS, the tracer concentration in plasma was significantly higher at 1 h and significantly lower at 4 and 24 h following dosing compared with placebo ( 81 ). Tracer concentration in the liver was significantly higher with NVAS compared with placebo at 4 to 15 h following dosing, did not differ between 1 and 4 d, and was again significantly higher 8–14 d postdosing.…”

“…Compared with placebo, NVAS increased the fractional release of VA from the liver, increased recycling of VA from organs to plasma, lowered the fractional loss of VA from organs, and affected other related kinetic parameters of VA metabolism. The uptake and turnover of modeled RBP-retinol and chylomicron-retinyl esters were altered in the stomach, intestine, liver, lung, kidney, and carcass with NVAS ( 81 ).…”