76 Nutrition Reviews, Vol. 56, No. 3 Special Article On the Methods for Studying the Mechanisms and Bioavailability of Iron Gladys Oluyemisi Latunde-Dada, Ph.D., Maria de Lourdes Pires Bianchi, Ph.D., and Jose Eduardo Dutra de Oliveira, M.D., Ph.D. March 1998: 76–80 Dr. Latunde-Dada is with the Department of Chemical Sciences, Agriculture University, Abeokuta, Nigeria. Dr. Bianchi is with the Faculty of Pharmaceutical Sciences and Prof. and Dr. Dutra de Oliveira is with the Faculty of Medicine, University of São Paulo, Ribeirao Preto, Brazil. Studies of the molecular mechanisms involved in the absorption and bioavailability of iron are important to attempts made worldwide to control the high incidence of iron-associated disorders. The ultimate objective of these studies is to develop methods that are relevant to iron bioavailability and interactions in humans. However, a comprehensive understanding of the chemical and physiologic mechanisms that influence iron bioavailability is necessary to achieve this goal. Initial studies using in vitro and animal models offer the potential for flexibility and manipulation of experimental variables that could provide valuable information toward the understanding and improvement of food iron bioavailability. Introduction The importance of iron nutrition and metabolism has been a subject of strong interest in both developing and devel- oped nations. 1–4 The metabolic disorders of iron represent a double-edged sword of deficiency and overload and have stimulated numerous interdisciplinary studies of the various aspects of iron’s nutrition, physiology, and bio- chemistry. Among these studies are two interrelated re- search interests. First, studies of dietary and physiologic factors that modulate the efficiency of iron absorption aim to formulate diets and dietary practices that enhance iron availability. 5,6 Second, an intensive search is under way to unravel the molecules, mode, and mechanisms of intesti- nal absorption of iron. 7–9 Despite many years of intensive studies, the path- ways and general features of intestinal iron absorption are still speculative and hypothetical. Consensus has not yet been reached on the comprehensive molecular mecha- nisms involved in iron passage into, across, and out of the mucosal epithelial cells. The unfolding scenarios of the transit of inorganic iron into the mucosal cell include three possibilities: (1) a paracellular uptake that is non- specific, nonregulated, and has a low affinity for iron per- meation, 10 (2) transcellular passive and partially regulated diffusion, 11 or (3) a highly regulated transcellular trans- port that might involve an electrogenic energy-requiring carrier-mediated pathway, 12 a glycoprotein, 13 fatty acid– mediated transport, 14 and/or the recently elaborated mucin-integrin-mobilferrin-paraferritin complex. 8,15 This last theory proposes that inorganic iron in the diet is chelated in vivo to luminal mucin to maintain its solubility at the neutral pH of the small intestine. 16 Iron is then transported across the mucosal microvillar membrane in association with a cell-surface integrin. 15 It is subse- quently transferred to a cytosolic mobilferrin 17 in associa- tion with paraferritin, 8 which is probably a ferrireductase. The emerging consensus, however, is that the reduction of Fe 3+ to Fe 2+ is a key regulatory step in the intestinal uptake of iron. The rate-determining reduction 18 occurs in the intestinal lumen or at the mucosal surface. This might also be a characteristic feature of the transferrin-indepen- dent iron uptake pathway elucidated in other mammalian tissues. 19,20 Iron Absorption The deluge of information generated thus far on the pro- cesses of intestinal iron absorption has been derived mostly from various in vitro model systems in animal cells or tissues. 8,12,17,21 These include the use of enterocytes, duodenal biopsies, brush border membrane vesicles, vas- cular perfused intestine, and everted intestinal sacs, rings, or loops. 22–24 These models have often been criticized on the basis of the disparities between the iron absorptive processes of laboratory animals, particularly rats, and hu- mans. 25,26 Such disparities include the observation that ascorbic acid and meat do not enhance iron absorption in the rat, 27,28 whereas they do in humans, as studies have © 1998 International Life Sciences Institute