Influence of vitamin A form and protein nature on the retinol status in the rat

In comparison with soybean proteins, the acid casein increases the blood and liver concentrations of retinol when the diet contains 1 mg of retinol/kg. The effect of the acid casein is more important when the vitamin A is supplied to rats as retinal: with the alcohol form, the amount of liver retinol is 88.7 micrograms; with the aldehyde form, it reaches 137 micrograms.     

Variation in retinol utilization rate with vitamin A status in the rat

The relationship of vitamin A status to retinol (ROH) utilization rate (disposal rate, DR) and other kinetic parameters was studied in rats with low (LO), marginal (MAR) or high (HI) mean liver vitamin A levels (2.2, 43 and 985 micrograms, respectively) and low or normal plasma ROH concentrations (6.8, 46 and 42 micrograms/dL). Kinetic parameters were calculated by input-output analysis of plasma [3H]ROH turnover monitored for 35 (LO and MAR) or 115 d (HI) after injection of [3H]ROH in its plasma transport complex. There was a highly significant negative correlation between fraction of dose in plasma 5 d after injection of [3H]ROH and the natural log of liver total vitamin A. The total time an average ROH molecule spent in plasma (residence time), as well as the time spent during each pass (transit time), was significantly lower in HI (0.77 d and 1.9 h) than in LO (0.98 d and 2.7 h) and MAR (0.92 d and 2.8 h) rats; however, the total time in the system (mean sojourn time) increased markedly with vitamin A status (5, 18 and 77 d). The number of times an average ROH molecule recycled through plasma before irreversible loss (7-9 times) was similar in all groups. Most of the ROH molecules (approximately 90%) that left the plasma were recycled, not irreversibly metabolized, in all groups. Among groups, ROH DR increased significantly from 1.2 (LO) to 8.0 (MAR) to 11.8 micrograms/d (HI). For LO versus MAR and LO versus HI, differences in DR were positively related to differences in the plasma ROH pool size. These results suggest that low plasma ROH concentrations are associated not only with low liver vitamin A levels, but also with a decreased ROH DR. This decreased DR may or may not reflect a compromised functioning of ROH-dependent systems.     

Biochemical but not clinical vitamin A deficiency results from mutations in the gene for retinol binding protein

BACKGROUND: Two German sisters aged 14 and 17 y were admitted to the Tübingen eye hospital with a history of night blindness. In both siblings, plasma retinol binding protein (RBP) concentrations were below the limit of detection (<0.6 micromol/L) and plasma retinol concentrations were extremely low (0.19 micromol/L). Interestingly, intestinal absorption of retinyl esters was normal. In addition, other factors associated with low retinol concentrations (eg, low plasma transthyretin or zinc concentrations or mutations in the transthyretin gene) were not present. Neither sibling had a history of systemic disease. OBJECTIVE: Our aim was to investigate the cause of the retinol deficiency in these 2 siblings. DESIGN: The 2 siblings and their mother were examined clinically, including administration of the relative-dose-response test, DNA sequencing of the RBP gene, and routine laboratory testing. RESULTS: Genomic DNA sequence analysis revealed 2 point mutations in the RBP gene: a T-to-A substitution at nucleotide 1282 of exon 3 and a G-to-A substitution at nucleotide 1549 of exon 4. These mutations resulted in amino acid substitutions of asparagine for isoleucine at position 41 (Ile41-->Asn) and of aspartate for glycine at position 74 (Gly74-->Asp). Sequence analysis of cloned polymerase chain reaction products spanning exons 3 and 4 showed that these mutations were localized on different alleles. The genetic defect induced severe biochemical vitamin A deficiency but only mild clinical symptoms (night blindness and a modest retinal dystrophy without effects on growth). CONCLUSIONS: We conclude that the cellular supply of vitamin A to target tissues might be bypassed in these siblings via circulating retinyl esters, beta-carotene, or retinoic acid, thereby maintaining the health of peripheral tissues.     

视黄醇结合蛋白、前白蛋白对胎儿宫内营养状况评估价值研究

目的 探讨视黄醇结合蛋白(RBP)、前白蛋白(PA)评价胎儿宫内营养状况的临床价值.方法 选择2015年在淮北市妇幼保健院分娩的338例新生儿作为研究对象,按胎龄分为早产儿组137例和足月儿组201例,生后12h内取静脉血检测RBP、PA水平,比较不同分组新生儿RBP、PA水平并分析RBP、PA水平对胎儿宫内营养状况的评价效果.结果 足月儿组血清RBP和PA水平均显著高于早产儿组(t值分别为5.548、4.337,均P<0.05),35~36周早产儿组血清RBP、PA水平均显著高于28~34周早产儿组(t值分别为5.097、9.007,均P<0.05),低体重儿组新生儿血清RBP、PA水平均显著低于其他两组RBP:t值分别为5.379、5.882,均P<0.05;PA:t值分别为6.498、7.267,均P<0.05),而巨大儿组新生儿血清RBP、PA水平均显著高于其他两组(t值分别为4.276、5.034,均P<0.05).结论 血清RBP、PA综合评价能够准确快速判断胎儿宫内营养状况,在临床上具有重要应用价值.     

Regulation of hepatic retinol metabolism: perspectives from studies on vitamin A status

Liver vitamin A (retinol) is obtained from several sources and is subject to multiple fates. Lecithin:retinol acyltransferase (LRAT), a microsomal enzyme present in liver and several other retinol-metabolizing tissues, esterifies retinol that is associated with a cellular retinol-binding protein, CRBP or CRBP-II. Recent research has shown that LRAT mRNA expression and enzyme activity are regulated in a tissue-specific manner. In vitamin A-deficient liver, both LRAT mRNA and activity are significantly down-regulated as well as rapidly induced after the administration of vitamin A or its principal hormonal metabolite, retinoic acid (RA). In long-term feeding studies and the metabolic steady state, liver LRAT is expressed dose-dependently across a wide range of dietary vitamin A. Additionally, an RA-inducible cytochrome P450, P450RAI or CYP26, is down-regulated in liver during vitamin A deficiency and up-regulated dose-dependently by dietary vitamin A and exogenous RA. Based on these results, we propose that LRAT and CYP26 serve as two molecular mechanisms, coordinately regulated by all-trans-RA, to control the availability of retinol and RA, respectively. The LRAT reaction, besides providing a readily retrievable storage form of vitamin A, may regulate the availability of retinol to other pathways, while the CYP26 reaction may serve to prevent a detrimental "overshoot" of RA concentration. Moreover, retinoid metabolism in the liver is likely to be closely integrated with that in peripheral tissues through the rapid interorgan transfer and recycling of retinoids, affecting the whole-body economy of vitamin A.     

Levels of vitamin A and cellular retinol binding protein in human hepatocellular carcinoma and adjacent normal tissue

The levels of vitamin A (retinol) and vitamin E were measured in the blood, in tissues of human hepatocellular carcinoma (HCC), and in adjacent liver parenchyma. The median values of vitamin A were 11.5 micrograms/g (ranging 0-82.5 micrograms/g) in HCC and 52.1 micrograms/g (ranging 0.4-895.2 micrograms/g) in normal liver tissues; the difference was statistically significant (p less than 0.05). By contrast, there was no significant difference in vitamin E levels between the two tissues. Although the levels of vitamin A were significantly lower in HCC in 10 patients, no significant difference was noted in the cellular retinol binding protein levels in the normal and malignant tissues. These results suggest that the decreased levels of vitamin A in HCC are not due to altered cellular retinol binding protein levels in tumors and the different vitamin A blood supply system. We conclude that either the decreased uptake of vitamin A, but not vitamin E, by HCC cells or the lack of vitamin A-storing cells in tumors might be responsible for the low levels of vitamin A in HCC.     

Effect of sow vitamin D status at parturition on the vitamin D status of neonatal piglets

The plasma concentrations of calcium, phosphorus, vitamin D, and vitamin D metabolites were determined in cholecalciferol-treated sows and untreated sows at parturition and their piglets (at birth and at 10 days of age) to determine the relationship between sow vitamin D status and neonatal piglet vitamin D status. At birth, there was a high degree of correlation between sow and piglet plasma concentrations of 25-hydroxycholecalciferol (r = 0.944), 24,25-dihydroxycholecalciferol (r = 0.895), and 25,26-dihydroxycholecalciferol (r = 0.737). Neonatal piglet plasma 1,25-dihydroxyvitamin D was low (42.0 +/- 10.2 pg/ml) and was not correlated with maternal plasma 1,25-dihydroxyvitamin D (r = 0.022). Neonatal plasma calcium and phosphorus were significantly correlated (P less than 0.05) with maternal plasma 1,25-dihydroxyvitamin D (r = 0.515 and 0.581, respectively). Parenteral cholecalciferol treatment of sows before parturition proved an effective means of supplementing young piglets with cholecalciferol (via the sow's milk) and its more polar metabolites via placental transport. However, it had no significant effect on either the plasma mineral or 1,25-dihydroxyvitamin D status of the sow or young piglet.     

Vitamin A, vitamin E, retinol binding protein (RBP), and prealbumin in digestive cancers

The existence of a relation between vitamin A and vitamin E and human cancers is supported by epidemiologic investigations. The aim of this study is to link the level of these vitamins to those of plasmatic protein carriers like retinol binding protein (RBP) and prealbumin (TTR), in three groups of subjects: healthy patients (n = 78), polyp (n = 34) and digestive cancer patients (n = 70). A paired t-test did not reveal any significant variation in any parameter between the polyp group and controls, but did evidence a significant decrease in serum levels of retinol (p less than 2.10(-4], RBP (p less than 2.10(-4), TTR (p less than 10(-5), and alpha-tocopherol (p less than 2.10(-3), in cancer cases as against control subjects. Comparison of RBP renal clearance and retinol tissue clearance in cancer and healthy patients indicates that the decrease in circulating retinol levels cannot be attributed to an increase in peripheral consumption. The simultaneous reduction of RBP and TTR serum levels is to be considered as a sign of protein denutrition. Thus our results suggest that the decrease serum levels of vitamins A and E observed in digestive cancers are a consequence of this nutritional deficiency.     

Effect of vitamin A supplementation with BCG vaccine at birth on vitamin A status at 6 wk and 4 mo of age

BACKGROUND: The effect of vitamin A supplementation (VAS) at birth on subsequent vitamin A status has not been studied. OBJECTIVE: The objective was to study the effect of 50,000 IU vitamin A administered with BCG vaccine at birth on vitamin A status in both sexes. DESIGN: Within a randomized placebo-controlled trial of VAS, we obtained blood from 614 children at 6 wk of age and from 369 mother-infant pairs at 4 mo of age. We assessed vitamin A status on the basis of serum retinol-binding protein (RBP) and measured serum C-reactive protein to monitor for concurrent infections. RESULTS: RBP concentrations indicated vitamin A deficiency in 32% of the children at age 6 wk and in 16% at age 4 mo. VAS was not associated with higher RBP concentrations overall or in either sex. However, the effect of VAS varied with maternal education (P for interaction = 0.004): At age 6 wk, VAS was associated with higher (9%; 95% CI: 2, 17%) RBP concentrations in children of noneducated mothers but not in children of educated mothers. Overall, RBP concentrations increased between 6 wk and 4 mo of age. The increase correlated inversely with the number of diphtheria-tetanus-pertussis (DTP) vaccines received in the interval (P = 0.009), particularly in girls (P for interaction = 0.01) and in vitamin A recipients (P = 0.01). CONCLUSIONS: Overall, VAS at birth had no effect on vitamin A status. However VAS may temporarily improve vitamin A status in the subgroup of children of noneducated mothers. In vitamin A recipients, subsequent DTP vaccines affected vitamin A status negatively. The main trial was registered at clinicaltrials.gov as NCT00168597.     

Effect of the maternal vitamin D status at parturition on the vitamin D status of the neonatal calf

The plasma concentrations of calcium, phosphorus, magnesium, hydroxyproline, vitamin D, and vitamin D metabolites were determined in cows and their colostrum-deprived calves. At birth, calf plasma calcium, phosphorus, and hydroxyproline concentrations were not correlated (P greater than 0.05) with the maternal plasma concentrations of these substances. There was a high degree of correlation between maternal and neonatal calf plasma concentrations of 25-hydroxyergocalciferol (r = 0.733), 25-dydroxycholecalciferol (r = 0.888), 24,25-dihydroxyergocalciferol (r = 0.770), 24,25-dihydroxycholecalciferol (r = 0.629), and 25,26-dihydroxycholecalciferol (r = 0.840). Neonatal calf plasma concentrations of 1,25-dihydroxyvitamin D were low (41.2 +/- 3.4 pg/ml) and had no correlation with maternal concentrations (r = 0.219, P greater than 0.05). Neonatal plasma calcium and inorganic phosphorus concentrations were correlated (P less than 0.05) with maternal plasma concentrations of 1,25-dihydroxyvitamin D (r = 0.559 and 0.525, respectively). Vitamin D status of the dam, therefore, appears to be important in determining neonatal calf plasma concentrations of 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, and 25,26-dihydroxyvitamin D, and, in addition, the plasma calcium and inorganic phosphorus status of the neonatal calf is apparently dependent on maternal concentrations of 1,25-dihydroxyvitamin D.     

The activity of acyl CoA: retinol acyltransferase in the rat: variation with vitamin A status

Retinol esterification in the small intestine, liver and kidney of rats given a normal diet or a vitamin-A-free diet and of rats given large doses of vitamin A was studied. The active enzyme is a microsomal acyl CoA:retinol acyl transferase (ARAT). In the small intestine ARAT activity was 0.37 nmol ester/mg microsomal protein per min. Large doses of vitamin A increased the activity significantly, while the enzyme activity in the vitamin-A-deficient rats was in the range of that of the controls. Retinoic acid in physiological doses (0.064 mg three times per week) had no influence on ARAT activity. In the liver, ARAT activity of the controls was 0.58 nmol ester/mg microsomal protein per min. The activity was increased after large doses of vitamin A. It was not significantly reduced in vitamin-A-deficient animals. The kidney had a low, but significant ARAT activity, both in normal and vitamin-A-deficient animals and after large doses of vitamin A (range 0.08-0.14 nmol ester/mg microsomal protein per min). The vitamin-A-esterifying enzyme in the small intestine and liver of the rat seems to be influenced by the amount of retinol in the diet.     

Significance of postprandial blood concentrations of retinol, retinol-binding protein, and carotenoids when assessing the vitamin A status of children

The effect of ingesting a breakfast rich in vitamin A on postprandial blood serum concentration of retinol, retinol-binding protein, and carotenoids has been investigated in children between 5 and 8 yr of age. They were divided by age in two groups (5 to 6 and 7 to 8 yr) and then randomly assigned in three groups to be studied cross-sectionally immediately before and at 2 and 4 h after the ingestion of a meal containing 337 micrograms of retinol equivalents (48% as retinol and 52% as carotenoids). The ingestion of breakfast did not alter significantly (p greater than 0.05) the postprandial serum concentrations of retinol, retinol-binding protein; or carotenoids in any of the age groups. These results indicate that up to 4 h the postprandial blood serum concentrations of these parameters are representative of their corresponding basal concentrations. Therefore, in practice and particularly under field survey conditions, the blood samples required to assess the vitamin A status of children can be obtained either fasting or within 4 h after breakfast without altering the results.     

Effect of vitamin A supplementation on haemoglobin and vitamin A levels during pregnancy

About 450 pregnant women from a low-income group were recruited to study the effect of vitamin A supplementation on plasma vitamin A levels in the mother and cord and on the birth weights of the neonates. Results showed that supplementation with 1800 micrograms vitamin A/d for more than 12 weeks prevented the decline in plasma vitamin A that otherwise occurs during the last few weeks of pregnancy. This improvement in maternal values for vitamin A at a critical time of development favourably affected availability to the fetus, as reflected by the marked elevation in cord levels. Supplementation for a period of 12 weeks was found to be sufficient, since subsequent discontinuation did not alter the beneficial response. Apart from increasing maternal and cord vitamin A levels, vitamin A supplementation along with iron prevented, in this study, the significant decline in haemoglobin occurring at 26-28 weeks of gestation. The birth weights were not altered by vitamin A supplementation.     

Serum levels of vitamin A and retinol binding protein in chronic renal patients treated by continuous ambulatorial peritoneal dialysis.

The possible causes and consequences of hypervitaminosis A and retinol binding protein (RBP) levels were investigated in patients with chronic renal disease submitted or not to dialysis treatment. The study was conducted on 20 patients divided into two groups: 10 patients with chronic renal failure (CRF) treated by continuous ambulatorial peritoneal dialysis (CAPD), and 10 CRF patients with no dialysis treatment. Ten normal subjects formed the control group. Retinol levels were determined by HPLC, and RBP levels by immunoassay in plasma and in post-dialysis fluid at different periods of time. Laboratory tests were carried out on all subjects, and dietary history was taken. Patients on dialysis had higher retinol levels than untreated patients. Retinol levels were found to be correlated with RBP levels. Serum retinol and RBP levels did not vary with diet, age or time of disease, dialysis group or time of dialysis, nor were they correlated with the levels measured in the dialysis fluid (CAPD). There was no significant correlation in retinol levels between chronic patients and controls. It is suggested that vitamin A and RBP clearances during dialysis do not accompany urea or creatinine clearance. Hypervitaminosis A did not show any toxic effect.     

Vitamin A supplementation of women postpartum and of their infants at immunization alters breast milk retinol and infant vitamin A status

Vitamin A supplementation of lactating mothers and of infants at the time of diphtheria-pertussis-tetanus (DPT) and oral polio vaccine (OPV) immunizations have both been suggested as measures to prevent deficiency among infants. This multicenter randomized, double-blind, placebo-controlled trial was conducted in Ghana, India and Peru to determine the effect of maternal vitamin A supplementation on breast milk retinol and of maternal and infant supplementation on infant vitamin A status. Mothers in the intervention group received 60 mg vitamin A (as retinol palmitate) at 18-42 d postpartum; their infants were given 7.5 mg three times, i.e., at 6, 10 and 14 wk of age with DPT and OPV immunizations. Mothers and infants in the comparison group received a placebo. Maternal supplementation resulted in higher breast milk retinol at 2 mo postpartum [difference in means 7.1, 95% confidence interval (CI), 3.4, 10.8 nmol/g fat] and lower proportion of mothers with breast milk retinol < or = 28 nmol/g fat (15.2 vs. 26.6%, 95% CI of difference -16.6, -4.1%). At 6 and 9 mo, maternal supplementation did not affect breast milk retinol or the proportion of mothers with low breast milk retinol. Vitamin A supplementation of the mothers and their infants reduced the proportion of infants with serum retinol < or = 0.7 micro mol/L (30.4 vs. 37%, 95% CI of difference -13.7, 0.6%) and that with low vitamin A stores as indicated by the modified relative dose response (MRDR) > 0.06 (44.2 vs. 52.9%, 95% CI of difference -16.6, -0.9%) at 6 mo. Supplementation had no effect at 9 mo. The beneficial effect of supplementation on breast milk retinol and infants' vitamin A status varied by site. It was greatest in India followed by Ghana and Peru. At the doses used, maternal supplementation improved breast milk retinol status at 2 mo (P < 0.001) and maternal and infant supplementation modestly increased (P = 0.03) infant vitamin A status at 6 mo of age. Additional strategies to improve vitamin A status of 6- to 9-mo-old infants must be considered.     

Anticonvulsant medication use and circulating levels of total thyroxine, retinol binding protein, and vitamin A in children with delayed cognitive development

Circulating thyroxine (T4), retinol binding protein (RBP), and vitamin A were measured in conjunction with nutritional status assessment of 707 cognitively delayed children, ages 3.0-9.0 y. Twenty percent were receiving anticonvulsant (AC) medication. T4 was lower and RBP and vitamin A were higher (p less than 0.0001) among AC than non-AC subjects. Molar ratios of vitamin A:RBP did not differ between the two groups nor did intakes of protein or vitamin A. Lower T4 and higher RBP were found among children who received diphenylhydantoin (DPH), phenobarbital, or AC combinations, but vitamin A was higher only among those who received DPH. RBP and vitamin A were lower (p less than 0.05) among children with infections and vitamin A was lower (p less than 0.05) among those with serum zinc less than 70 micrograms/dL (less than 10.7 mumol/L); differences between AC and non-AC subjects remained when other variables were considered.     

Levels of vitamin a and cellular retinol binding protein in human hepatocellular carcinoma and adjacent normal tissue

The levels of vitamin A (retinol) and vitamin E were measured in the blood, in tissues of human hepatocellular carcinoma (HCC), and in adjacent liver parenchyma. The median values of vitamin A were 11.5 μg/g (ranging 0–82.5 μg/g) in HCC and 52.1 μg/g (ranging 0.4–895.2 μg/g) in normal liver tissues; the difference was statistically significant (p < 0.05). By contrast, there was no significant difference in vitamin E levels between the two tissues. Although the levels of vitamin A were significantly lower in HCC in 10 patients, no significant difference was noted in the cellular retinol binding protein levels in the normal and malignant tissues. These results suggest that the decreased levels of vitamin A in HCC are not due to altered cellular retinol binding protein levels in tumors end the different vitamin A blood supply system. We conclude that either the decreased uptake of vitamin A, but not vitamin E, by HCC cells or the lack of vitamin A‐storing cells in tumors might be responsible for the low levels of vitamin A in HCC.     

Effect of supplementation with vitamin A or plant carotenes on plasma retinol levels among young Egyptian males

Thirteen young Egyptian males with initial low plasma retinol level were divided into three groups and received single oral vitamin A dose of 200,000 IU, or carotene supplement in the form of boiled spinach leaves, providing roughly 617 RE/day or carrots providing 394 RE/day. The three supplements were equally effective, when the plasma retinol level was measured 40 days later. On a price basis, the vitamin A capsules and the carrots were much cheaper than the spinach supplement.     

Effect of vitamin E supplementation on vitamin K status in adults with normal coagulation status

BACKGROUND: Cases of enhanced anticoagulant effect in response to high-dose vitamin E supplementation have been reported among patients taking oral anticoagulants. Although a vitamin E-vitamin K interaction was proposed to underlie this effect, it has not been systematically investigated in adults with normal baseline coagulation status. OBJECTIVE: The objective was to study the effect of 12 wk of supplementation with 1000 IU RRR-alpha-tocopherol/d on biochemical measures of vitamin K status in men and women not taking oral anticoagulants. DESIGN: Vitamin K status, which was assessed with the use of plasma phylloquinone concentrations, the degree of under-gamma-carboxylation of prothrombin (proteins induced by vitamin K absence-factor II, PIVKA-II), and the percentage of undercarboxylated osteocalcin (ucOC), was determined in 38 men and women with rheumatoid arthritis (study A) and in 32 healthy men (study B) participating in 2 independent, 12-wk randomized clinical trials of vitamin E supplementation (1000 IU/d). RESULTS: Mean (+/- SD) PIVKA-II increased from 1.7 +/- 1.7 to 11.9 +/- 16.1 ng/mL (P < 0.001) in study A and from 1.8 +/- 0.6 to 5.3 +/- 3.9 ng/mL (P < 0.001) in study B in response to 12 wk of vitamin E supplementation. An increase in PIVKA-II is indicative of poor vitamin K status. In contrast, the other measures of vitamin K status (ie, plasma phylloquinone concentration and percentage of ucOC) did not change significantly in response to the supplementation. CONCLUSIONS: High-dose vitamin E supplementation increased PIVKA-II in adults not receiving oral anticoagulant therapy. The clinical significance of these changes warrants further investigation, but high doses of vitamin E may antagonize vitamin K. Whether such an interaction is potentially beneficial or harmful remains to be determined.