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The Nutrition Research Program, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4
* To whom correspondence should be addressed. E-mail: sinnis{at}cw.bc.ca.
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ABSTRACT |
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 TOP ABSTRACT IntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
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Introduction |
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TOPABSTRACTIntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
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Choline is an essential dietary nutrient that plays a critical role as a component of phosphatidylcholine, thus functioning in membrane lipids, lipoproteins, bile lipid, and lung surfactant, in the neurotransmitter acetylcholine, and as a precursor to betaine, which functions as a source of labile methyl groups (12). The metabolism of choline intersects with the methionine-homocysteine cycle at 2 steps (Fig. 1). The sequential transfer of methyl groups from S-adenosylmethionine (SAM) to phosphatidylethanolamine by phosphatidylethanolamine-N-methyl transferase (PEMT) leads to de novo synthesis of choline in phosphatidylcholine (PC) (13). PC can also be formed via cytidine diphosphocholine, but this pathway requires preformed choline derived from the diet or the PEMT pathway. The other product of PEMT is S-adenosylhomocysteine (SAH), which is converted to homocysteine. Homocysteine is further metabolized by remethylation to methionine, or homocysteine can enter the transsulfuration pathway, which leads to cysteine, a precursor of reduced glutathione (GSH) (14). The folate-dependent pathway for remethylation of homocysteine involves 5,10-methylenetetrahydrofolate reductase (MTHFR) and methionine synthase, and is usually considered the major pathway. In the folate-independent pathway, betaine-homocysteine S-methyltransferase (BHMT) transfers methyl groups from betaine to homocysteine to regenerate methionine with dimethylglycine as the other product (Fig. 1) (15). Betaine is synthesized from choline by choline oxidase and betaine adehyde dehydrogenase. Further metabolism of dimethylglycine generates two 1-carbon units, thereby recovering all 3 methyl groups donated from SAM to form choline (16,17). The MTHFR and BHMT pathways show reciprocal interaction such that choline oxidase and BHMT activities are increased when the MTHFR pathway is limiting; in contrast, choline deficiency results in an increased utilization of folate (12,18–21).
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Subjects and Methods |
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TOPABSTRACTIntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
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This study was approved by the University of British Columbia's Clinical Screening Committee for Research and Other Studies Involving Human Subjects and the British Columbia Children's and Women's Hospital Research Coordinating Committee. All the parents and children provided written informed consent.
Blood collection. For this study, venous blood was collected from each child as one 7-mL blood sample into tubes containing EDTA as the anticoagulant. The samples were centrifuged, prepared into aliquots for individual testing, and frozen at –70°C within 20 min of blood collection (6,26).
Analytical methods.
Plasma choline, betaine, and dimethylglycine were determined using isotope dilution liquid chromatography tandem mass spectrometry (LC-MS/MS) based on Holm et al. (27) with modification for our instrumentation and use of N-dimethyl d6-glycine HCl as an internal standard, in addition to betaine-d9 HCl and choline-d9 chloride (CDN Isotopes). The mass spectrometer is a Quattro Micro tandem MS configured with an electrospray source coupled to a 2790 Alliance HPLC equipped with a thermostatted autosampler (Waters Corporation). The mass spectrometer was operated in positive ion electrospray multiple reaction monitoring (MRM) mode using the transitions of m/z 118 
59 (betaine), m/z 127 68 (betaine-d9), m/z 104 60 (choline), m/z 113 69 choline-d9, m/z 104 58 (dimethylglycine), and m/z 110 64 (dimethyl-d6-glycine). The LC was equipped with a Rx-Sil 2.1 x 150 mm column packed and a precolumn 2.1 x 12.5 mm, both with 5 µm packing (Agilent Technologies).
For analysis, 50 µL of plasma or aqueous standard was transferred to a 1.5 mL Eppendorf tube containing 10 µL of internal standards and vortexed. Protein was precipitated by adding 100 µL of acetonitrile containing 0.1% formic acid, the samples were centrifuged (2600 x g for 15 min, at 5°C), and 20 µL of supernatant was transferred to an autosampler vial containing 20 µL mobile phase. The chromatographic separation was carried out isocratically at a flow of 0.5 mL/min with a mobile phase consisting of 19% 15 mmol/L ammonium formate, 0.1% formic acid in H20, and 81% acetonitrile. The autosampler and column were maintained at 10°C and 25°C, respectively. A sample volume of 4 µL was used for analysis, with a total analytical time of 7.0 min.
Plasma thiols were determined by reverse-phase ion-pairing HPLC with electrochemical detection (28,29), and the plasma and red cell folate and plasma vitamin B-12 were quantified using Quantaphase II radioimmunoassay (Bio-Rad Laboratories) as described previously (26).
Statistical analysis. All data were analyzed using the Statistical Package for Social Sciences (SPSS for Windows, version 10.0, SPSS). Data are presented as means ± SEM. Independent 2-tailed t tests were used to compare the results of children with CF and the control children. Pearson correlation coefficients were calculated to determine potential associations among plasma choline, betaine, and dimethylglycine and the plasma methionine, homocysteine, and the SAM:SAH ratio. P < 0.05 was considered significant.
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Results |
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TOPABSTRACTIntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
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F508 mutation; 1 child was homozygous for the G85E mutation, and 1 child was G542x/G5511D. The weight, height, and body mass index (kg/m2) of children with CF were 47.5 ± 0.4 kg, 147.6 ± 0.4 cm, and 18.3 ± 0.3, respectively, and for the control children were 58.4 ± 5.2 kg, 161.8 ± 6.0 cm, and 21.2 ± 1.1, respectively. The children with CF had a mean hemoglobin of 135.5 ± 1.1 g/L, and the mean hemoglobin for controls was 141.0 ± 2.4 g/L. We found no evidence of folate or vitamin B-12 deficiency among children with CF, which is consistent with the use of multivitamin supplements in our CF clinic. Rather, the children with CF had higher plasma (8.29 ± 0.38 nmol/L), red blood folate (119 ± 11.6 nmol/L), and plasma vitamin B-12 (855 ± 72.3 pmol/L) concentrations than control children who had concentrations of 4.56 ± 0.38 nmol/L, 129 ± 8.20 nmol/L, and 383 ± 32.7 pmol/L, respectively, P < 0.05. The plasma concentrations of choline, betaine, and dimethylglycine in the children with CF were significantly lower than in the healthy, control children (Table 1). We calculated the ratios of choline:betaine and betaine:dimethylglycine as indices of the oxidation of choline to betaine and of the BHMT-dependent remethylation of homocysteine, respectively (Table 1). The ratios of choline:betaine and betaine:dimethylglycine did not differ between children with CF and the control children. As in our previous studies (26), children with CF had significantly higher plasma homocysteine, SAH, and adenosine, but lower methionine and SAM:SAH and GSH:oxidized glutathione (GSSG) ratios than children without CF, P < 0.05.
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Discussion |
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TOPABSTRACTIntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
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10 µmol/L among adult men that decreased by 30% following 5 wk of consuming a diet devoid of choline (30). In the present study, the plasma choline level in children with CF was 6.53 ± 0.32 µmol/L and was 27% lower than in healthy children without CF; it was also lower than reported for adult men consuming a diet devoid of choline (30). In addition, because of ethics and practical reasons related to the conduct of studies with young children, blood samples were not collected after an overnight fast, which raises the possibility that differences in diet could explain the lower choline in children with CF compared with children without CF. However, individuals with CF are advised to consume dietary fat intakes of 35–40% total energy, an intake above the intake of fat suggested for the general population (31), and, in a previous study, we showed total fat intakes of 35% total energy, with mean intakes of choline of 460 mg/d among children with CF compared with 374 mg/d among children without CF (6), similar to the Dietary Reference Intake (DRI) for choline (32). This suggests that the low choline status in children with CF is not explained by a lower or inadequate intake of choline.
The extent to which the lower plasma choline in children with CF contributes to or is the result of increased plasma homocysteine in these children is an important question. The metabolism of choline intersects with the methionine-homocysteine cycle at the de novo synthesis of choline, in which the sequential methylation of phosphatidylethanolamine with methyl groups derived from methionine via SAM, catalyzed by PEMT, leads to the formation of PC, and through the betaine-dependent remethylation of homocysteine (Fig. 1). An increase in SAM:SAH in children with CF, as shown in Innis et al. (26; Table 1), can result in reduced activity of several methyltransferases, including PEMT (14,33), which raises the possibility that de novo synthesis of choline is reduced in CF secondary to the increased homocysteine and decreased SAM:SAH. Possible explanations for the elevated homocysteine associated with CF (6,26) include deficiencies of folate, vitamin B-12, and vitamin B-6, decreased remethylation secondary to defects in MTHFR, methionine synthase, methionine synthase reductase, or defects in cystathionine ß-synthase leading to reduced entry of homocysteine into the trans-sulferation pathway (14). In addition, oxidative stress is known to occur in CF (34–36), and, in the present study, the plasma GSH:GSSG ratio was 75% lower in children with CF than in the controls. The reductive methylation of homocysteine to methionine using 5-methyltetrahydrofolate is accomplished by methionine synthase and involves the generation of Cob(I)alamin, a highly reactive and unstable form of vitamin B-12 that is particularly susceptible to oxidation (37). However, defects in the remethylation and trans-sulferation pathway are usually associated with large increases in plasma homocysteine (14), whereas the increase in plasma homocysteine in children with CF found in our study is modest. Furthermore, due to reciprocal interaction of the MTHFR and BHMT pathways, in presence of adequate choline, reduced remethylation of homocysteine via the MTHFR pathway is accompanied by increased choline oxidase and BHMT activity, thus involving increased synthesis of betaine and dimethylglycine (12,19,20,38–40). In the present study, we found no evidence of increased betaine or dimethylglycine in children with CF; rather, the plasma betaine and dimethylglycine concentrations were 35% lower in children with CF than in the control children. We calculated the plasma choline:betaine and betaine:dimethylglycine ratios as possible indices of the oxidation of choline to betaine and the BHMT-dependent remethylation of homocysteine to methionine. Our results show no significant difference in the plasma choline:betaine or betaine:dimethylglycine ratios between children with CF and healthy children. We believe these results suggest that the low choline status in children with CF are not explained by the increased conversion to betaine to support BHMT-dependent remethylation of homocysteine, secondary to reduced activity of the MTHFR pathway, further suggesting no impairment to the remethylation of homocysteine via the MTHFR pathway.
Our finding of a significant positive relation between choline and methionine and between betaine and methionine are consistent with the findings of other recent studies that suggest the BHMT pathway for remethylation of homocysteine is important in the regeneration of methionine (19,38,39). Similarly, the inverse association between dimethylglycine and homocysteine shown in the present study is consistent with the generation of dimethylglycine in the BHMT dependent remethylation of homocysteine, although no significant relation was found between the plasma dimethylglycine and methionine, or between betaine and homocysteine. However, previous studies in adults have shown an inverse association of plasma homocysteine with betaine (39) and of choline with homocysteine, betaine, and dimethylglycine in pregnant women (40).
In our study, despite higher plasma and red blood cell folate concentrations, children with CF had increased plasma homocysteine and reduced plasma methionine, SAM:SAH, choline, and betaine, compared with children without CF. The GSH:GSSG ratio is often used as an indicator of the cellular redox status and, in normal individuals, the plasma GSH:GSSG ratio is >10 (41). In our study, the GSH:GSSG ratio in children with CF was only 25% that of healthy children, consistent with other reports of oxidative stress in CF (34–36). Choline deficiency has been shown to result in a decrease in liver SAM in animals (12,22). Of relevance, SAM is a positive modulator of cystathionine ß-synthase, thus also serving to regulate the entry of homocysteine into the trans-sulferation pathway, which leads to cysteine, the rate limiting precursor for synthesis of GSH (14,42,43). However, further research is needed to address whether changes in methionine-homocysteine metabolism in children with CF might contribute to the concomitant low GSH status.
In summary, the present studies provide clear evidence of low choline, betaine, and dimethylglycine status in children with CF. Together with our previous reports of increased fecal PC and lysoPC excretion and increased plasma homocysteine and reduced plasma SAM:SAH (6,26), these findings suggest that functional choline deficiency, with depletion of methyl groups and elevated homocysteine, is possibly due to both impaired absorption (6) and inhibition of PEMT activity that are secondary to the decreased plasma SAM:SAH (14,33). In addition to steatosis, several other clinical complications, including osteoporosis, certain cancers, and altered biophysical and immunological properties of pulmonary surfactant, are known to occur with increased frequency in CF (5,10,11,44–48). Our studies suggest the need to consider the possibility that choline depletion and altered thiol metabolism may contribute to or exacerbate some of the complications associated with CF.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Abbreviations used: BHMT, betaine-homocysteine S-methyltransferase; CF, cystic fibrosis; CFTR, transmembrane conductance regulator; GSH, reduced glutathione; GSSG, oxidized glutathione; MTHFR, methylene tetrahydrofolate reductase; SAM, S-adenosylmethionine; PC, phosphatidylcholine; PEMT, phosphatidylethanolamine-N-methyltransferase; SAH, S-adenosylhomocysteine.
Manuscript received 13 March 2006. Initial review completed 11 April 2006. Revision accepted 19 May 2006.
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LITERATURE CITED |
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