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Reduction of Fe(III) Is Required for Uptake of Nonheme Iron by Caco-2 Cells^1,2,3,

Department of Food, Nutrition and Food Service Management, The University of North Carolina, Greensboro, NC 27412 ^* Nutrient Requirements and Function Laboratory, Beltsville Human Nutrition Research Center, U.S. Department of Agriculture-Agricultural Research Service, Beltsville, MD 20705

Differentiated cultures of Caco-2 human colonic cells were used to examine the importance of reduction of nonheme ferric iron, Fe(III), for transport across the brush border surface. Cultures accumulated 100 pmol Fe/(h·mg protein) when 10 µmol Fe(III) as the nitrilotriacetic acid complex (1Fe:2NTA) was added to the apical compartment. Ascorbic acid enhanced cellular acquisition of iron in a dose-dependent manner, with a concentration as low as 8 µmol/L ascorbate increasing iron uptake by 50%. Similarly, the rate of iron transport from the apical to the basolateral compartment increased 5.6- and 30-fold when 100 and 1000 µmol/L ascorbic acid, respectively, were present in the apical chamber. Ascorbate-medicated stimulation of iron uptake was temperature dependent and required the reduction of Fe(III) to Fe(II), because it was inhibited by ascorbate oxidase and chelators of Fe(II). Moreover, Caco-2 cells recycled dehydroascorbic acid to ascorbic acid. Ferricyanide and Fe(II) chelators also partially inhibited iron uptake from a medium devoid of ascorbic acid. Intact Caco-2 cells exhibited a ferrireductase activity on the apical surface that accounted for the majority of iron accumulated by cells incubated in the absence of exogenous reductant. These data suggest that reduction of Fe(III) within the lumen or at the cell surface is required for transfer of this essential micronutrient across the intestinal brush border surface.

KEY WORDS: • Caco-2 human cell line • ferrireductase • iron absorption • ascorbic acid

¹ Preliminary report of this research was presented at Experimental Biology 94, April 24–28, 1994, Anaheim, CA [Han, O., Failla, M. L., Hill, A. D., Morris, E. & Smith, J. C., Jr. (1994) Reduction of Fe(III) is required for uptake by human Caco-2 cells. FASEB J. 8: A921 (abs.), and in the AIN Graduate Student Research Award Competition].

² Supported in part by North Carolina Agriculture Experiment Station.

³ The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.

⁴ To whom correspondence should be addressed.

Manuscript received 18 July 1994. Revision accepted 9 November 1994.

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