Increased vitamin E intake is associated with higher a-tocopherol concentration in the maternal circulation but higher a-carboxyethyl hydroxychroman concentration in the fetal circulation1–3 Svetlana Didenco, Melanie B Gillingham, Mitzi D Go, Scott W Leonard, Maret G Traber, and Cindy T McEvoy ABSTRACT Background: The transfer of vitamin E across the placenta is limited, but no data exist on the concentrations of vitamin E metabolites carboxyethyl hydroxychromans (a- and c-CEHCs) in the fetal circulation. Objective: We measured a- and c-CEHC concentrations in maternal and umbilical cord blood pairs and examined their relations to circulating vitamin E (a- and c-tocopherol) and maternal dietary vitamin E intake. Design: Healthy, pregnant women were enrolled from Oregon Health and Science University’s obstetric clinic (,22 wk gestation), and at least one fasting blood sample and a previous day’s 24-h diet recall were collected during their pregnancy (n = 19). Umbilical cord blood samples were obtained at the time of delivery and were analyzed for a- and c-tocopherol, a- and c-CEHC, and total lipid concentrations. Results: Mean (6SD) concentrations of umbilical cord blood a-CEHC (30.2 6 28.9 nmol/L) and c-CEHC (104.5 6 61.3 nmol/L) were not significantly different from maternal concentrations (P = 0.07 and 0.08, respectively), but metabolite:tocopherol ratios were significantly higher in cord blood (P , 0.01 and 0.001, respectively). Maternal a-tocopherol:total lipids ratios were correlated with cord blood a-CEHCs (r = 0.67, P = 0.004), and higher vitamin E intakes were associated with higher cord blood a-CEHC concentrations (r = 0.75, P , 0.003). Conclusion: Higher maternal intake of vitamin E during pregnancy may result in increased metabolite concentrations in the fetal circulation, suggesting increased maternal or fetal liver metabolism of vitamin E. This trial was registered at clinicaltrials.gov as NCT00632476. Am J Clin Nutr 2011;93:368–73.
during pregnancy may increase fetal stores and prevent fetal vitamin E deficiency symptoms (4). The effects of vitamin E supplements during pregnancy on fetal vitamin E stores would depend on placental transfer of the vitamin. Low fetal vitamin E concentrations at birth suggest a limited transfer across the placenta, estimated to be only 10% of the passively transferred L-glucose (5). In animal and human studies, pregnant mothers given labeled vitamin E had increased deuterated a-tocopherol concentrations, but transfer of the label to the fetus was limited and selective for the natural RRR steroisomer (6, 7). Limited maternal-fetal transfer may be a combination of inefficient placental transfer of plasma lipids and the steroselective transport of only the 2R-a-tocopherols (1, 7). Recently, the stereoselective transporter, a-tocopherol transfer protein (a-TTP), was isolated from human placental trophoblast cells, and may be responsible for this selective placental transfer (8). The placenta may also restrict vitamin E passage to prevent its accumulation by the fetus. Recent reports have suggested that vitamin E supplementation during gestation is associated with in utero growth restriction (9, 10). Vitamin E does not accumulate in the liver, but rather the liver degrades it to carboxyethyl hydroxychromans (CEHCs) (11). The proposed pathway involves an initial step of x-oxidation by the cytochrome P450 (CYP) enzyme system, followed by consecutive steps of b-oxidation (12). The only P450 enzyme that has been shown to perform the x-oxidation of tocopherols and tocotrienols is CYP4F2 (13, 14). If the fetal liver is incapable of active xenobiotic metabolism, then limitation of the transfer of excess nutrient may be important. Conversely, the fetal liver may metabolize the vitamin
INTRODUCTION
1 From the Graduate Programs in Human Nutrition (SD and MBG), the Department of Molecular and Medical Genetics (MBG), and the Department of Pediatrics (MDG and CTM), School of Medicine, Oregon Health and Science University, Portland, OR; and the Linus Pauling Institute, Oregon State University, Corvallis, OR (SWL and MGT). 2 Supported by NIH grant K23 NHLBI HL080231 and the Oregon Clinical and Translational Research Institute (OCTRI); grant no. ULI RR024140 from the National Center for Research Resources, a component of the NIH and the NIH Roadmap for Medical Research; and the Linus Pauling Institute. 3 Address correspondence to CT McEvoy, Department of Pediatrics, Mail Code CDRC-P, 3181 SW Sam Jackson Park Road, Oregon Health and Science University, Portland, OR 97239. E-mail:
[email protected]. Received April 6, 2010. Accepted for publication November 23, 2010. First published online December 15, 2010; doi: 10.3945/ajcn.110.008367.
It is thought that infants, especially preterm infants, are born with deficient plasma vitamin E concentrations compared with their mothers (1, 2). Treating preterm infants with pharmacologic vitamin E doses has been proposed to prevent or limit associated vitamin E deficiency conditions such as retinopathy, intracranial hemorrhage, hemolytic anemia, and chronic lung disease. However, the 2003 Cochrane review on vitamin E supplementation of preterm infants (3) concluded that high-dose supplementation resulting in concentrations .3.5 mg/dL (81 lmol/L) are associated with an increased incidence of sepsis. The same report suggested that maternal supplementation of vitamin E
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VITAMIN E METABOLITES IN FETAL CIRCULATION
directly. Several reports have found P450 enzyme activity in human fetal liver (15, 16). We hypothesized that the placenta limits vitamin E transfer to the fetus by selective transfer of the RRR steroisomer to the fetus or that the fetal liver actively metabolizes the vitamin. Therefore, the purpose of this study was to determine vitamin E and a- and c-CEHC concentrations in umbilical cord blood compared with maternal blood concentrations. a- and c-CEHCs have not been previously investigated in fetal circulation or during pregnancy. The results of this study have implications for the proposed practice of supplementing pregnant mothers with vitamin E for the purpose of increasing fetal vitamin E stores (1). SUBJECTS AND METHODS
Subjects Nonsmoking pregnant mothers (n = 19) were recruited from the Oregon Health and Science University (OHSU; Portland, OR) obstetrical clinics during their routine prenatal visits as part of a larger ongoing study (NCT00632476; http://clinicaltrial. gov/ct2/show/NCT00632476). The inclusion and exclusion criteria for the subjects are listed in Table 1, and eligibility was assessed using the patient’s electronic chart information. The OHSU Institutional Research Board approved the study, and a written informed consent was obtained from each subject. Study design At least one fasting blood draw (1 mL) and a previous day’s 24-h diet history were obtained during the course of the pregnancy in coordination with the participant’s prenatal appointments. At delivery, an umbilical cord blood sample was obtained from the participant’s infant. Both the maternal and cord blood specimens were collected into evacuated tubes containing 1 mg EDTA/mL, centrifuged (5 min, 2500 · g, 4°C) to separate plasma, and frozen at 280ºC until analysis. Demographic, anthropometric, and delivery outcome variables were obtained from OHSU’s electronic charting system. Prenatal vitamin use was determined by a questionnaire administered to the participant by research personnel. Nutrient intake data obtained from the 24-h dietary recalls were calculated by using Nutrition Data System for Research (NDSR, 2006 and 2007; University of Minnesota, St
Paul, MN), estimating dietary intake of total vitamin E (a- and c-tocopherols), total fat, total cholesterol, and energy. Laboratory analyses Tocopherols were extracted from plasma according to the methods of Podda et al (17) by using HPLC with amperometric detection. a- and c-CEHCs were separated by reverse-phase HPLC (18) and quantified by single quadrupole mass spectrometric detection (19). Briefly, the CEHC samples were incubated at 37ºC for 30 min with 100 lL b-glucuronidase enzyme solution, 20 lL H2O containing 1% ascorbic acid, and an internal standard (Trolox; Sigma-Aldrich, St Louis, MO). The samples were then acidified with 10 lL of 12-mol/L HCl and extracted with 5 mL of diethyl ether. An aliquot of the ether layer was then dried under nitrogen gas, resuspended in H2O: MeOH (1:1, by vol) containing 0.1% (by vol) acetic acid, and injected into the HPLC system (Waters 2690 Separation Module; Waters Corporation, Milford, MA), equipped with a SymmetryShield RP-18 column 3.5-lm particle size (Waters Corporation; 4.6 · 75 mm). Samples were detected using a Waters Micromass ZQ2000 single-quadrupole mass spectrometer with an electrospray ionization probe. Analyte retention times were as follows: a-CEHC, 15.57 min; c-CEHC, 14.70 min; and Trolox, 14.60 min. Metabolite concentrations were calculated relative to known standards. Lipid panels including total cholesterol and triglycerides were measured by autoanalyzer. Total lipids were determined by the sum of the plasma triglycerides and cholesterol. Tocopherol:total lipid ratios were determined by dividing tocopherol concentrations by the total lipid sum. Statistical analysis STATA (version 11.0; StataCorp, College Station, TX) was used to perform statistical analyses. A P value of ,0.05 was considered significant for all performed tests. A total of 19 pairs of maternal and umbilical cord blood samples were collected during the course of the study, but 2 of the umbilical cord blood values were determined to be significant outliers. These samples had plasma concentrations consistent with maternal concentrations and could have been incorrectly labeled. Therefore, they were removed from the data set and only 17 pairs of maternal and umbilical cord blood samples were used for the statistical
TABLE 1 Inclusion and exclusion criteria1 Inclusion criteria 1. Maternal age of 15 y 2. Pregnant with consent and enrollment/random assignment before 22 wk gestation by LMP and confirmed by ultrasound when available 3. History of never smoking with confirmatory urine cotinine 4. Singleton gestation 5. Informed consent signed
1
LMP, last menstrual period.
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Exclusion criteria 1. Multiple gestation 2. Documented major fetal congenital anomalies 3. Current maternal use of heroin, cocaine, crack, LSD, or methamphetamines 4. Recent history of alcohol abuse: .3 drinks on .5 d/wk since LMP, hospitalization for alcohol abuse 5. Continuous use of daily high-dose vitamin C or vitamin E supplements since LMP 6. History of kidney stones 7. Maternal unstable psychiatric illness or inability to confirm stable residence 8. Insulin-dependent diabetic
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analysis. Furthermore, one cord blood sample had an inadequate amount of plasma for total lipid analysis; hence, 16 pairs were used for a/c-tocopherol:total lipids ratio analyses. Differences between maternal and umbilical cord blood concentrations of tocopherol and tocopherol:total lipid ratios were calculated with a one-tailed, paired Student’s t test. Differences in CEHC concentrations and tocopherol:CEHC ratios were assessed with a two-sided, paired Student’s t-test. Pearson’s correlation analysis was used to assess possible relations between maternal and umbilical cord blood biochemical variables and to determine possible associations in plasma and dietary tocopherol. If extreme points in the data were identified, correlation analysis was also performed by using the nonparametric Spearman’s test, which is insensitive to extreme points. If both the Pearson’s and Spearman’s correlations led to the same conclusion, the Pearson’s correlation is presented.
RESULTS
The average age of the participating mothers was 29 y, and the majority were white and primigravid. The range of their prepregnancy body mass index (in kg/m2) was 16–36. All deliveries were uncomplicated, at 38 wk gestation, and the majority were vaginal deliveries. The mean infant birth weight was 3.5 6 0.5 kg (Table 2). The average (6SD) time between admission to the hospital and the actual delivery was 12.7 6 8.8 h. No significant associations were observed between the newborn’s birth weight or the type of delivery and cord plasma variables. Tocopherol and CEHC concentrations were measured in both maternal and umbilical cord blood pairs (Table 3). Both a- and c-tocopherol concentrations were significantly lower in cord blood compared with maternal blood (P , 0.001). After correction for lipid concentrations, the tocopherol:total lipids ratios remained significantly lower in cord blood [a-tocopherol:total lipids (P , 0.001) and c-tocopherol:total lipids (P , 0.005)]. Absolute a- and c-CEHC concentrations were not significantly different between maternal and cord blood values (P = 0.07 and 0.08, respectively), but there was a trend for lower concentrations in cord blood. Importantly, the metabolite:tocopherol ratios were significantly different; both the a-CEHC:a-tocopherol and c-CEHC:c-tocopherol ratios were higher in the cord blood (P , 0.01 and ,0.001, respectively). We also investigated possible associations between maternal and umbilical cord blood biochemical variables (Table 4). There were no significant correlations between maternal and umbilical TABLE 2 Characteristics of participating mothers (n = 19) and their delivery outcomes Value Age (y) White [n (%)] Health profession [n (%)] Primigravidas [n (%)] Prepregnancy BMI (kg/m2) Length of gestation (wk) Vaginal delivery [n (%)] Infant birth weight (kg) 1
Mean; range in parentheses (all such values).
29 14 6 12 25 40 13 3.5
(22–36)1 (74) (32) (63) (19–36) (38–41) (68) (2.3–4.4)
cord plasma a-tocopherol concentrations (r = 0.41, P = 0.11), but after adjustment for total lipids the association became significant (r = 0.64, P = 0.008). Neither cord blood c-tocopherol nor c-tocopherol:total lipids ratios were significantly correlated with maternal concentrations (r = 0.45, P = 0.08, and r = 0.13, P = 0.63, respectively). Also, the higher a-tocopherol:total lipids ratio in maternal blood was reflected by an increase in the fetal metabolite concentration of a-CEHC (r = 0.67, P = 0.004; Figure 1). To adjust for the nonnormal distribution, both a- and c-CEHC concentrations were log transformed. A strong correlation was observed between maternal and cord blood a-CHEC and c-CEHC concentrations (r = 0.70, P =0.002, and r = 0.70, P =0.002, respectively). No other associations between maternal and cord plasma reached statistical significance. The dietary intake analysis was based on 16 maternal 24-h diet histories (Table 5). The vitamin E from prenatal vitamins was obtained from the follow-up questionnaire, which was administered by study personnel, and was based on 13 responses. The total vitamin E was calculated as the vitamin E intake from food (measured by NDSR) combined with vitamin E from prenatal vitamins. Maternal a-tocopherol was significantly correlated with dietary vitamin E from food (r = 0.63, P = 0.009) and vitamin E from food plus prenatal supplements (r = 0.56, P = 0.04). Maternal a-CEHC concentrations were also significantly correlated with dietary vitamin E and vitamin E from food plus prenatal supplements (r = 0.50, P = 0.04, and r = 0.62, P = 0.02, respectively). On the contrary, cord blood plasma a-tocopherol concentrations were not correlated with maternal dietary vitamin E intake. Cord blood a-CEHC concentrations were significantly correlated with maternal dietary vitamin E from food (r = 0.69, P = 0.003) and total vitamin E from food plus prenatal supplements (r = 0.75, P , 0.003) (Figure 2). DISCUSSION
Measurement of CEHC has been used to assess vitamin E metabolism in human studies. This is the first report of CEHC concentrations in cord blood, and the results obtained show similar CEHC concentrations in maternal and cord blood samples. Because the fetal circulating vitamin concentrations were lower, the a-CEHC:a-tocopherol ratios in the fetal circulation were triple those in the maternal circulation. Interestingly, cord blood a-CEHC was significantly correlated with maternal total dietary vitamin E, whereas maternal vitamin E intake was not significantly correlated to the cord plasma tocopherol concentrations. Therefore, it seems that within our relatively small range of vitamin E intakes, a higher intake of vitamin E during pregnancy results in elevated metabolite concentrations in fetal blood, without increasing the fetal blood vitamin E concentration. Dietary intakes of vitamin E greater than those reported in this study during pregnancy may increase fetal a-tocopherol concentrations as shown by Acuff et al (7). We cannot determine from this study if the source of the CEHC metabolite was maternal liver, fetal liver, or placenta. We measured a- and c-CEHC concentrations in 2 placental tissue samples and observed very low concentrations of the metabolite in placental tissue (SWL and MGT, unpublished observation, May 2010). To date, no studies have reported that CYP4F2 is expressed in placental tissue (20). Further studies are warranted, but current evidence
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VITAMIN E METABOLITES IN FETAL CIRCULATION TABLE 3 Maternal and umbilical cord plasma concentrations of total lipids, tocopherol, and carboxyethyl hydroxychroman (CEHC) and ratios of tocopherol:total lipids and CEHC:tocopherol n Total lipids (mmol/L)2 a-Tocopherol (lmol/L) a-Tocopherol:total lipids (lmol/mmol) c-Tocopherol (lmol) c-Tocopherol:total lipids (lmol/mmol) a-CEHC (nmol/L) c-CEHC (nmol/L) a-CEHC:a-tocopherol c-CEHC:c-tocopherol 1 2 3 4 5
Maternal
16 17 16 17 16 17 17 — —
8 33.4 4.3 1.9 0.25 50.4 141.7 1.6 86.8
6 6 6 6 6 6 6 6 6
13 7.7 0.6 0.7 0.08 52.0 78.5 1.9 64.4
P1
Cord 2 6.7 3.1 0.4 0.17 30.2 104.5 5.7 389.6
6 6 6 6 6 6 6 6 6
0.5 2.5 1.0 0.2 0.08 28.9 61.3 5.5 291.5
, , , , ,
0.0014 0.0014 0.0014 0.0014 0.0054 0.075 0.085 , 0.015 , 0.0015
P , 0.05 was considered significant. Total lipids determined as triglycerides + total cholesterol. Mean 6 SD (all such values). Determined by one-sided paired t test. Determined by two-sided paired t test.
does not suggest that the placenta accumulates CEHC metabolites or expresses the known tocopherol metabolizing P450 enzyme CYP4F2. The data suggest that the placenta is most likely not a site of active metabolism. It is also plausible that the water-soluble a-CEHCs pass the placental barrier to the fetus, equilibrating with the maternal circulation. During phase II metabolism of xenobiotics in the liver, a bulky endogenous compound is conjugated to the site of the oxidation, such as glucuronate or sulfate, before hepatic excretion, making the metabolite highly polar and water soluble, thus requiring special transporter proteins to pass the cell membrane. Multidrug resistance–associated proteins are thought to be one group of enzymes that regulate the efflux of conjugated metabolites from the liver and have also been located in the placental syncytiotrophoblast membrane (21). a-CEHC could be transported into the fetal circulation by using these transporters. It is possible that the metabolites possess some biological role and might be necessary for fetal development. For example, some antioxidant activity has been associated with CEHC in vitro (22). On the contrary, it is also possible that the metabolite produced by the fetal liver is transported back into the maternal circulation for excretion, which could explain the observed higher a-CEHC concentrations in pregnant women compared with the previously determined nonpregnant normal adult values (23, 24). In addition to drug and vitamin E metabolism, P450 enzymes play an important role in the synthesis
of 20-hydroxyeicosatetraenoic acid (20-HETE) production, an arachidonic acid derivative regulating vascular tone and endothelial function (25). It is possible the fetal liver metabolizes tocopherols along with arachidonic acid via the CYP4F family of enzymes in utero (15, 26). Further studies are needed to test this possibility. In the present study, both a- and c-tocopherol concentrations were ’5 times lower in cord blood compared with maternal plasma and remained significantly lower when expressed as the tocopherol:total lipids ratio. No significant correlations were observed between maternal and cord plasma a- and c-tocopherol concentrations. However, after adjustment for total lipids, the cord blood a-tocopherol:total lipids ratio correlated with the maternal ratio. Although most studies found no significant association in a-tocopherol concentrations between maternal and cord blood (2, 27–30), there is some disparity in the relation of a-tocopherol after adjustment for lipids. Yeum et al (30) assessed the relations of tocopherols in healthy, pregnant women at delivery and in cord blood pairs and observed a positive correlation in c-tocopherol concentrations between maternal and cord plasma (r = 0.808, P = 0.0047) but none for a-tocopherol concentrations or a-tocopherol adjusted for triglyceride concentrations. Oostenbrug et al (28) observed no correlation either
TABLE 4 Correlations between maternal and umbilical cord tocopherol and carboxyethyl hydroxychroman (CEHC) concentrations r1 a-Tocopherol a-Tocopherol:total lipids c-Tocopherol c-Tocopherol:total lipids a-CEHC3 c-CEHC3 1 2 3
Pearson’s correlation. P , 0.05. Log transformed.
0.41 0.642 0.45 0.13 0.702 0.702 FIGURE 1. Correlation between maternal a-tocopherol:total lipids ratio and umbilical cord a-carboxyethyl hydroxychroman (a-CEHC). n = 16; r = 0.67, P = 0.004.
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TABLE 5 Dietary intake summary of participating mothers Value1
n Energy (kcal) Fat (g) Total cholesterol (mg) Vitamin E (IU)2 a-Tocopherol (mg) c-Tocopherol (mg) Prenatal vitamin E (IU) Total vitamin E (IU)3 1 2 3
16 16 16 16 16 16 13 13
1963 71 266 13 8.1 12.5 30 43
(1573–2761) (34–130) (116–1023) (3–44) (1.4–22.7) (3.1–34.9) (11–100) (14–144)
Values are means; ranges in parentheses. Vitamin E from food. Vitamin E from food + prenatal vitamin.
between a-tocopherol concentrations or between c-tocopherol concentrations. On the other hand, Jain et al (27) observed no correlation between a-tocopherol in maternal circulation and paired cord plasma, but after normalization for total lipids in the blood the relations became significant (r = 0.54, P = 0.007). Our present study did not show a significant correlation in c-tocopherol concentrations between maternal and cord samples probably due to the small sample size of the study. Furthermore, it is well documented that plasma and tissue c-tocopherols are suppressed by a-tocopherol supplementation, and because the participants took prenatal vitamins that contained varied amounts of either RRR- or all-rac-a-tocopherol forms this might explain the lack of an association between maternal and cord blood c-tocopherol concentrations. The a-tocopherol intakes could have suppressed c-tocopherol concentrations to varying degrees. The previous studies mentioned above did not discuss participants’ prenatal vitamin use. In conclusion, a- and c-tocopherol concentrations were significantly lower in cord blood than in maternal blood, even after adjustment for total lipids. Of the tocopherols, only a-tocopherol: total lipids ratio was significantly correlated between maternal and cord blood concentrations. The absolute vitamin E metabolite concentrations, a- and c-CEHC, were not significantly different between maternal and fetal circulations, but the metabolite:tocopherol ratios were significantly higher in cord blood. The higher a-tocopherol:total lipids ratio in maternal blood was reflected by an increased a-tocopherol:total lipids
ratio in fetal blood, and an even more prominent increase in the fetal metabolite concentration of a-CEHC. Furthermore, increased vitamin E intake was associated with higher a-tocopherol concentration in the maternal circulation but higher a-CEHC concentration in the fetal circulation, suggesting that higher amounts of dietary vitamin E may result in increased metabolism of the vitamin, possibly by the maternal or fetal liver. If the goal of supplemental vitamin E in pregnancy is to increase fetal stores, it appears that current routine prenatal supplements do not increase the fetal circulating tocopherol concentrations but may increase their metabolite concentrations. Supplementation with RRR-a-tocopherol or higher doses of vitamin E may be necessary to significantly increase fetal tocopherol concentrations. A recent study randomly assigned .10,000 pregnant women to vitamin supplements that included 400 IU vitamin E compared with placebo in the attempt to prevent pregnancy-associated hypertension (31). Cord tocopherol concentrations were not measured in that study, but it is interesting to note that the high doses of vitamin E given throughout the pregnancy did not lower the incidence of possible vitamin E deficiency conditions such as retinopathy of prematurity, respiratory distress, or intraventricular hemorrhage. It is possible that fetal a-tocopherol concentrations were not significantly higher in infants born to mothers who were supplemented than in controls. It is also possible that increased fetal a-tocopherol concentrations do not prevent these neonatal complications and intakes higher than the Recommended Dietary Allowance (15 mg RRR-a-tocopherol) are not of benefit. Further studies are needed to examine the relation of maternal vitamin E supplements and their effect on the fetus. We are extremely grateful to Nakia Clay for assistance in recruitment of participants and data collection. We are also grateful to the pregnant women and their infants for their participation in this study. The authors’ responsibilities were as follows—SD, MBG, SWL, MGT, and CTM: formulated the specific hypothesis of the study, which was conducted within an ongoing, larger randomized trial; SD, MDG, and CTM: participated in patient consent, data collection, and follow-up; SD, MGB, and MGT: analyzed the data and drafted the manuscript; and SD, SWL, and MGT: measured vitamin E and its metabolites. All authors participated in preparing the final draft of the manuscript. None of the authors had a financial or personal conflict of interest related to this research or its source of funding.
REFERENCES
FIGURE 2. Correlation between maternal total vitamin E intake and umbilical cord a-carboxyethyl hydroxychroman (a-CEHC). n = 13; r = 0.75, P , 0.003.
1. Debier C. Vitamin E during pre- and postnatal periods. Vitam Horm 2007;76:357–73. 2. Kiely M, Cogan PF, Kearney PJ, Morrissey PA. Concentrations of tocopherols and carotenoids in maternal and cord blood plasma. Eur J Clin Nutr 1999;53:711–5. 3. Brion LP, Bell EF, Raghuveer TS. Vitamin E supplementation for prevention of morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2003;CD003665. 4. Rumbold AR, Crowther CA, Haslam RR, Dekker GA, Robinson JS. Vitamins C and E and the risks of preeclampsia and perinatal complications. N Engl J Med 2006;354:1796–806. 5. Schenker S, Yang Y, Perez A, et al. Antioxidant transport by the human placenta. Clin Nutr 1998;17:159–67. 6. Lauridsen C, Engel H, Jensen SK, Craig AM, Traber MG. Lactating sows and suckling piglets preferentially incorporate RRR- over allrac-alpha-tocopherol into milk, plasma and tissues. J Nutr 2002;132: 1258–64. 7. Acuff RV, Dunworth RG, Webb LW, Lane JR. Transport of deuteriumlabeled tocopherols during pregnancy. Am J Clin Nutr 1998;67: 459–64.
VITAMIN E METABOLITES IN FETAL CIRCULATION 8. Rotzoll DE, Scherling R, Etzl R, Stepan H, Horn LC, Poschl JM. Immunohistochemical localization of alpha-tocopherol transfer protein and lipoperoxidation products in human first-trimester and term placenta. Eur J Obstet Gynecol Reprod Biol 2008;140:183–91. 9. Aris A, Leblanc S, Ouellet A, Moutquin JM. Detrimental effects of high levels of antioxidant vitamins C and E on placental function: considerations for the vitamins in preeclampsia (VIP) trial. J Obstet Gynaecol Res 2008;34:504–11. 10. Poston L, Briley AL, Seed PT, Kelly FJ, Shennan AH. Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet 2006;367:1145–54. 11. Traber MG, Burton GW, Hamilton RL. Vitamin E trafficking. Ann N Y Acad Sci 2004;1031:1–12. 12. Galli F, Cristina Polidori M, Stahl W, Mecocci P, Kelly FJ. Vitamin E biotransformation in humans. Vitam Horm 2007;76:263–80. 13. Sontag TJ, Parker RS. Cytochrome P450 omega-hydroxylase pathway of tocopherol catabolism. Novel mechanism of regulation of vitamin E status. J Biol Chem 2002;277:25290–6. 14. Sontag TJ, Parker RS. Influence of major structural features of tocopherols and tocotrienols on their omega-oxidation by tocopherolomega-hydroxylase. J Lipid Res 2007;48:1090–8. 15. Leeder JS, Gaedigk R, Marcucci KA, et al. Variability of CYP3A7 expression in human fetal liver. J Pharmacol Exp Ther 2005;314: 626–35. 16. Stevens JC, Hines RN, Gu C, et al. Developmental expression of the major human hepatic CYP3A enzymes. J Pharmacol Exp Ther 2003; 307:573–82. 17. Podda M, Weber C, Traber MG, Packer L. Simultaneous determination of tissue tocopherols, tocotrienols, ubiquinols, and ubiquinones. J Lipid Res 1996;37:893–901. 18. Lodge JK, Traber MG, Elsner A, Brigelius-Flohe R. A rapid method for the extraction and determination of vitamin E metabolites in human urine. J Lipid Res 2000;41:148–54. 19. Himmelfarb J, Kane J, McMonagle E, et al. Alpha and gamma tocopherol metabolism in healthy subjects and patients with end-stage renal disease. Kidney Int 2003;64:978–91. 20. Prouillac C, Lecoeur S. The role of the placenta in fetal exposure to xenobiotics: importance of membrane transporters and human models for transfer studies. Drug Metab Dispos 2010;38:1623–35.
373
21. St-Pierre MV, Serrano MA, Macias RI, et al. Expression of members of the multidrug resistance protein family in human term placenta. Am J Physiol Regul Integr Comp Physiol 2000;279:R1495–503. 22. Betancor-Fernandez A, Sies H, Stahl W, Polidori MC. In vitro antioxidant activity of 2,5,7,8-tetramethyl-2-(2’-carboxyethyl)-6-hydroxychroman (alpha-CEHC), a vitamin E metabolite. Free Radic Res 2002;36:915–21. 23. Galli F, Lee R, Dunster C, Kelly FJ. Gas chromatography mass spectrometry analysis of carboxyethyl-hydroxychroman metabolites of alpha- and gamma-tocopherol in human plasma. Free Radic Biol Med 2002;32:333–40. 24. Radosavac D, Graf P, Polidori MC, Sies H, Stahl W. Tocopherol metabolites 2, 5, 7, 8-tetramethyl-2-(2’-carboxyethyl)-6-hydroxychroman (alpha-CEHC) and 2, 7, 8-trimethyl-2-(2’-carboxyethyl)-6-hydroxychroman (gamma-CEHC) in human serum after a single dose of natural vitamin E. Eur J Nutr 2002;41:119–24. 25. Stec DE, Roman RJ, Flasch A, Rieder MJ. Functional polymorphism in human CYP4F2 decreases 20-HETE production. Physiol Genomics 2007;30:74–81. 26. Nishimura M, Yaguti H, Yoshitsugu H, Naito S, Satoh T. Tissue distribution of mRNA expression of human cytochrome P450 isoforms assessed by high-sensitivity real-time reverse transcription PCR. Yakugaku Zasshi 2003;123:369–75. 27. Jain SK, Wise R, Bocchini JJ Jr. Vitamin E and vitamin E-quinone levels in red blood cells and plasma of newborn infants and their mothers. J Am Coll Nutr 1996;15:44–8. 28. Oostenbrug GS, Mensink RP, Al MD, van Houwelingen AC, Hornstra G. Maternal and neonatal plasma antioxidant levels in normal pregnancy, and the relationship with fatty acid unsaturation. Br J Nutr 1998; 80:67–73. 29. Sanchez-Vera I, Bonet B, Viana M, Sanz C. Relationship between alpha-tocopherol content in the different lipoprotein fractions in term pregnant women and in umbilical cord blood. Ann Nutr Metab 2004;48: 146–50. 30. Yeum KJ, Ferland G, Patry J, Russell RM. Relationship of plasma carotenoids, retinol and tocopherols in mothers and newborn infants. J Am Coll Nutr 1998;17:442–7. 31. Roberts JM, Myatt L, Spong CY, et al. Vitamins C and E to prevent complications of pregnancy-associated hypertension. N Engl J Med 2010;362:1282–91.
