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United States Department of Agriculture

Agricultural Research Service


item Hunt, Janet

Submitted to: American Journal of Clinical Nutrition
Publication Type: Other
Publication Acceptance Date: January 13, 2005
Publication Date: May 1, 2005
Citation: Hunt, J.R. 2005. Letter to the editor: absorption of iron from ferritin. American Journal of Clinical Nutrition. 81(5):1178-79.

Technical Abstract: Your Manuscript Number (MS #) is: 21351, Version 1 Letter to the Editor: Absorption of Iron from Ferritin Dear Sir: I would like comment on the paper, 'Iron in ferritin or in salts (ferrous sulfate) is equally bioavailable in nonanemic women' by P. Davila-Hicks, E. C. Theil, and B. Lonnerdal (1). The conclusion indicated in the title is based on measurements of iron absorption from horse spleen ferritin that was radiolabeled in vitro, and appears to contrast with the results of others whose studies using ferritin radiolabeled in vivo were not cited (2-4). For example, Skikne and colleagues (4) also found that iron from ferritin radiolabeled in vitro was absorbed similarly to iron from ferrous sulfate. However, the same group further reported that radioiron incorporated into bovine spleen ferritin in vivo was significantly less absorbed than iron from ferrous sulfate: (respectively) 3.2 vs. 8.2% from a 3 mg dose with food, 3.8 vs. 24.1% from the 3 mg without food, 0.6 vs. 2.6 from 50 mg with food, and 0.7 vs. 7.9 from 50 mg without food (4). Those who have studied ferritin radiolabeled in vivo have concluded that ferritin iron is poorly absorbed, and that it is not part of the nonheme pool of dietary iron that is readily exchangeable in and similarly absorbed from the intestinal lumen (2-4). For instance, in vivo-labeled ferritin 59Fe was only 36% as well absorbed as 55Fe from intrinsically labeled soybeans consumed in the same meal (2). Its possible that lower absorption of ferritin-iron may explain the slightly increased (10%) absorption of nonheme iron from extrinsic over intrinsically labeled foods (5), which would suggest that the ferritin-iron content of the foods is only a minor portion of total food iron. It is worth noting that the ferritin iron content of foods has not been widely determined because of the lack of species-specific antibodies as well as the insolubility and possible time-dependent molecular changes that may make ferritin iron less exchangeable (6). Each labeling method has potential problems. On the one hand, the in vivo labeling of animal ferritin has in some (2, 4), but not all (3) reports involved procedures to limit the radiolabel incorporation into blood by reducing erythrocyte synthesis or increasing erythrocyte breakdown, and it is not known whether these techniques may alter ferritin isomerization. It is clear that the in vivo procedure does not uniformly label all of the iron in ferritin, but this would not necessarily explain the reduced iron bioavailability, as the portion that is unlabeled may be less, not more exchangeable/absorbable. On the other hand, the in vitro labeling results in higher bioavailability whether the ferritin has first been depleted of iron (1) or not (4), and in vitro iron exchange can induce ferritin degradation through Fenton chemistry (6). Skikne et al. (4) observed a minor small molecular peak in the Sepharose 6B elution pattern of in vitro, but not in vivo labeled ferritin, that they proposed to be denatured ferritin. Those investigators (4) determined that in vitro procedures labeled a full range of isoferritins, but with slightly higher isotope incorporation into the more acidic forms (4). It is unlikely that horse spleen ferritin labeled with extra phosphorus in vitro (1) is comparable to plant ferritin. Using Mössbauer spectroscopy, Ambe et al. (7) found that the form of ferric iron, representing about 95% of the iron in soybeans, was clearly distinguishable from, but more similar to horse spleen ferritin than to ferric phytate. Although physicochemical methods detected only minor alterations in ferritin labeled in vitro (1, 4), the human absorption results provide a distinguishing bioassay for ferritin labeled in vitro vs. in vivo. Davila-Hicks et al. (1) proposed that a high absorption of iron from the Tokyo soybean cultivar is partially explained by a high ferritin content of this cultivar, in addition to the low iron status of the subjects (8). After logarithmic transformations of both variables, absorption of iron is inversely related to body iron stores, varying 10-15 fold between subjects (see Figure 1a of (9)). This relationship alone is sufficient to account for the differences in iron absorption from soybeans cited by Davila-Hicks et al. (1): 26% by women with borderline iron deficiency (assuming 80% RBC incorporation of absorbed isotope) (8), 20% by women with iron deficiency (assuming 100% RBC incorporation; the absorption calculation is increased to 25% if assuming 80% RBC incorporation) (10), and 2.8% by iron-replete men (11). Lacking a direct comparison of cultivars with the same subjects, the similar results obtained by Murry-Kolb et al. (8) and Sayers et al. (10) do not support the hypothesis that the iron from the high-ferritin Tokyo soybean cultivar was more bioavailable than commonly used soybean cultivars. Davila-Hicks et al (1) concluded that iron from ferritin or ferrous sulfate follow different metabolic pathways after absorption. This was based on similarities in iron absorption when measured by whole body scintillation counting (22 and 22% from ferritin vs. ferrous sulfate, respectively, Table 1) but differences in the absorption when measured from erythrocyte iron incorporation (27 and 48%). The greater retention of isotope in the erythrocytes than in the whole body suggests methodological difficulties. The specific method and assumptions used were not delineated. With commonly used methods (see citations in (9)) and an assumption of 80% incorporation of the absorbed isotope into blood, we have repeatedly obtained similar absorption results between the two methods, including results with added ferrous sulfate (9). For instance, nonheme iron absorption from a hamburger meal supplemented with 20 mg iron as ferrous sulfate was 8.4 % (6.8, 10.3) (geometric mean plus and minus 1 SE) by whole body counting (see data in Figure 1a of (9)) and 8.5 % (6.7, 10.7) by the erythrocyte incorporation method, and the assumption of 80% incorporation of the absorbed isotope into blood was confirmed (9). Using data from individual subjects (n=23), the blood incorporation method was highly correlated to the whole body count method (R2 = 0.98) (9). These data do not confirm the finding that iron from ferrous sulfate is more extensively incorporated into blood than is apparent from whole body counting measurements. In conclusion, research on iron bioavailability from ferritin labeled in vitro must be interpreted with caution. The evidence does not support the conclusion that iron absorbed from ferrous sulfate follows a different metabolic distribution than iron absorbed from ferritin. References 1. Davila-Hicks P, Theil EC, Lonnerdal B. Iron in ferritin or in salts (ferrous sulfate) is equally bioavailable in nonanemic women. Am J Clin Nutr 2004;80:936-40. 2. Layrisse M, Martinez-Torres C, Renzy M, Leets I. Ferritin iron absorption in man. Blood 1975;45:689-98. 3. Derman DP, Bothwell TH, Torrance JD, et al. Iron absorption from ferritin and ferric hydroxide. Scand J Haematol 1982;29:18-24. 4. Skikne B, Fonzo D, Lynch SR, Cook JD. Bovine ferritin iron bioavailability in man. Eur J Clin Invest 1997;27:228-33. 5. Cook JD, Layrisse M, Martinez-Torres C, Walker R, Monsen E, Finch CA. Food iron absorption measured by an extrinsic tag. J Clin Invest 1972;51:805-815. 6. Laulhere JP, Laboure AM, Briat JF. Mechanism of the transition from plant ferritin to phytosiderin. J Biol Chem 1989;264:3629-35. 7. Ambe S, Ambe F, Nozaki T. Mössbauer study of iron in soybean seeds. J Agric Food Chem 1987;35:292-296. 8. Murray-Kolb LE, Welch R, Theil EC, Beard JL. Women with low iron stores absorb iron from soybeans. Am J Clin Nutr 2003;77:180-4. 9. Hunt JR, Zeng H. Iron absorption by heterozygous carriers of the HFE C282Y mutation associated with hemochromatosis. Am J Clin Nutr 2004;80:924-31. 10. Sayers MH, Lynch SR, Jacobs P, et al. The effect of ascorbic acid supplementation on the

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