Riboflavin Transport at other Sites and Storage

As mentioned earlier, nearly all tissues require ribo-flavin. The free vitamin is trapped as one of its phosphorylated coenzyme forms, which then become specifically associated (and in a few cases covalently linked) to the protein chains of catalytic flavoenzymes. If not already covalently linked, the flavin coenzyme can often be liberated by extremes of pH or by other nonphysiological maneuvers. In a few biological locations, such as the mature red cell, fla-voenzymes such as glutathione reductase (NADPH: oxidized glutathione oxidoreductase EC 1.6.4.2) may exist partly in their apoenzyme form, i.e., without the flavin coenzyme and therefore without enzyme activity. An increased supply of riboflavin will permit the depleted coenzyme (in this case FAD) to be synthesized so that enzyme activity can be restored.

Different enzymes and different tissue sites differ in the tenacity with which they can retain flavin coenzymes in times of riboflavin deficiency, so there is a characteristic 'pecking order' for flavoen-zyme protection, which appears to reflect the metabolic importance of the different metabolic pathways affected. Apart from this 'pecking order,' however, there is no repository of unused or nonfunctional riboflavin that can act as a 'store' in times of dietary deficiency. Although some organs (such as liver) have relatively high concentrations of flavin enzymes, all of the flavin seems to be present as coenzyme moieties of flavin holoenzymes. Each tissue has a characteristic 'ceiling' level of riboflavin at saturation, and a 'floor' level characteristic of severe depletion, and these are determined, respectively, by the total amount of apoflavoprotein, and the amount of 'resistant' holoenzyme, which cannot be depleted of its cofactor during riboflavin deficiency.

Riboflavin is secreted into milk, the concentration being species specific and to a moderate extent dependent on maternal status and intake. Riboflavin is also required by the developing fetus during pregnancy, which implies a need for active transport from the maternal to the fetal circulation; the flavin concentration being greater on the fetal side. Studies from India have identified a riboflavin carrier protein (RCP) present in bird (e.g., chicken) eggs, which is considered to be specific for riboflavin, and is essential for normal embryological development. If this protein is rendered ineffective (e.g., by immuno-neutralization) by treatment of the bird with a specific antibody, then embryonic development ceases and the embryo dies. A genetic mutant lacking RCP is likewise infertile. A homologous protein, which can be rendered ineffective by the antibody to pure chicken riboflavin carrier protein, has been shown to occur in several mammalian species, including two species of monkeys, and also in humans. Very recent studies have suggested that circulating RCP levels and the immunohistochemical staining of RCP in biopsy specimens may provide new markers for breast cancer diagnosis and prognosis. Termination of pregnancy has been demonstrated by immuno-neutralization of RCP in monkeys. There remains some controversy over the roles of RCP, however, and other, less specific riboflavin binders in blood, including gamma-globulins, also seem to play an important role. These studies have provided an intriguing example of the role of specific vitamin-transporting mechanisms, designed to ensure that the vitamin needs of the developing embryo will be efficiently met. Further evidence of the special needs of developing embryos has been provided by the demonstration that riboflavin analogs can cause teratogenic changes, even in the absence of any detectable damage to maternal tissues.

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