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LETTER TO THE EDITOR |
Department of Food Science and Human Nutrition
University of Florida
210 FSHN Newell Drive
Gainesville, FL 32611-0370
E-mail: ylam{at}ufl.edu
Institute of Nutrition and Food Sciences
Pathophysiology of Nutrition
University of Bonn
Bonn
Germany
Dear Sir:
In our recent report in the Journal (1), we presented a working model for the appearance of the B-vitamin folate in red blood cells (RBCs) and for its elimination from RBCs. RBC folate is used as indicator of long-term folate status. To our knowledge, no data so far have described the amount of time needed for RBC folate to become saturated after supplementation or high intake of folate, folic acid, or both.
We are grateful for the opportunity to underline the purpose of our kinetic model. Quinlivan questions the validity of applying the pharmacokinetic approximation that saturation of RBC folate occurs after 5 half-lives of RBCs. Quinlivan also emphasizes that "RBC turnover does not follow first-order kinetics." This is a well-established fact, which is based on the finite lifetime of the RBCs. We acknowledge that our pharmacokinetic approach is based on first-order kinetics. Clearly, RBCs have a finite life span that, by definition, is not truly a first-order process. However, our model describes folate concentration in RBCs that is related to a whole-body folate pool and that stays in interaction with multiple other tissues. We consider erroneous Quinlivan's assumption that, after degradation of RBCs, all of their folate content will be washed out of the body. Alternatively, we suggest that at least a portion of the folate from spent RBCs re-enters the folate pools, especially at high intakes of reduced folate, folic acid, or both, and that it can be incorporated into newly developing RBCs. Therefore, we suggest that the elimination of RBC folate is exponential rather than linear. Regardless of the kinetic model, a simple approximation as presented in our report appears to be entirely reasonable. It is important to differentiate between this working model based on such approximations and other working models based solely on observed turnover rates of labeled folate in RBCs.
We consider the comparison of our model with the model by Lin et al (2) to be inappropriate. Lin et al (2) used a single bolus of radiolabeled folate to quantify human folate kinetics, and they described a linear decrease in RBC folate concentrations by measuring the specific activity of RBCs. Our concern about their model is that the linear decrease in RBC folate concentrations can be explained by the fact that only a single bolus of radiolabeled folate was given and thereby incorporated into RBCs. Although it is likely that radiolabeled folate re-entering the pool after RBC degradation will be re-incorporated in RBC development, such recycling would be minor relative to the total RBC folate appearance. Thus, the specific activity of RBC folate decreases with the degradation of RBCs and, because RBC degradation is linear, the specific activity for RBC folate over time is measured to be linear. Kinetic analysis of the disappearance of RBC folate derived from such bolus-dose studies provides very useful kinetic information about RBC folate and its relation to the finite lifetime of RBCs. However, such an analysis is not necessarily informative about the rate of saturation of RBC folate under conditions of supplementation. In addition, such analysis does not preclude the use of a working descriptive model based on a whole-body assumption of first-order kinetics.
We acknowledge that the classic publication of Herbert (3) showed a linear decrease in RBC folate concentrations during severe folate depletion. However, in that single-subject experiment, the diet was severely deficient in folate (5 µg folate/d), whereas the subjects in our study had an average intake of 250 µg folate/d. During the extreme folate depletion in the study by Herbert, body folate pools would have declined precipitously. It is likely that, under such conditions, folate from degrading RBCs would re-enter the whole-body folate pool and be used for other critical purposes, such as maintaining nucleotide synthesis and methylneogenesis reactions. Our model has little bearing on RBC folate kinetics in conditions of outright deficiency. Rather, our model describes the situation of cessation of supplementation with folate, folic acid, or both—ie, a cessation of folate intake high above the average—whereupon a normal folate intake through an adequate diet would remain constant. As described in our report, the model is consistent with RBC folate kinetics observed in 2 independent, well-controlled intervention studies that measured the increase in RBC folate after 16–24-wk supplementation with folate, folic acid, or both.
Quinlivan also states that we "assumed that the RBC folate concentration had not reached a maximum after 24 wk of supplementation." This criticism is incorrect, however, because we suggested that RBC folate concentrations increase after 24 wk and plateau only after 5 half-lives of RBCs, as presented in the model. Because the intervention ended after 24 wk, we could not determine (and we did not wish to assume or state) whether this happened in the suggested way. Clearly, 5 half-lives of RBCs would exceed the 24-wk observation period and, obviously, would also exceed the lifetime of RBCs. Our model serves as a hypothesis of possible RBC folate kinetics both during long-term intake of supplements of folate, folic acid, or both and after cessation of such supplementation, which would, by necessity, involve dynamics between RBC kinetics and whole-body folate kinetics.
Quinlivan further comments that a steady state of RBC folate may have been reached between weeks 16 and 24. In our intervention study, blood drawings were performed every 4 wk, and RBC folate significantly increased between week 16 and week 20 and between week 20 and week 24 (4). This continuous increase was observed in all 3 supplementation groups that received either 400 µg folic acid/d, 416 µg [6S]-5-methyltetrahydrofolate/d, or 208 µg [6S]-5-methyltetrahydrofolate/d (4). To our knowledge, no intervention study has yet been conducted to measure the long-term effect of supplementation with folate, folic acid, or both on saturation kinetics of RBC folate. To date, the longest intervention trials lasted 24 wk, and neither of those trials (4, 5) could determine a plateau in RBC folate concentration. Meanwhile, Quinlivan states that it will take 
21 wk for RBC folate to reach steady state. He explains that "plateau RBC folate enrichment may be further delayed by the amount of time it takes for the RBC progenitor cells, presumably in the bone marrow, to reach maximum enrichment." This statement supports our hypothesis that RBC folate concentrations plateau later than after 24 wk of supplementation.
In conclusion, we wish to emphasize that our model is in fact a testable hypothesis that suggests a possible description for the behavior of RBC folate during and after long-term supplementation with folate, folic acid, or both. The appearance of RBC folate in the model is partly confirmed by 2 independent studies, and the kinetic model for RBC folate elimination is currently being tested in a long-term intervention trial.
ACKNOWLEDGMENTS
Neither of the authors had a personal or financial conflict of interest.
REFERENCES
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