Regulation of intestinal vitamin B(2) absorption. Focus on "Riboflavin uptake by human-derived colonic epithelial NCM460 cells".

RIBOFLAVIN OR VITAMIN B2 (7,8-dimethyl-10-ribitylisoalloxazine) is an essential water-soluble vitamin. Riboflavin is important for normal cell functioning and for cell growth and development. Riboflavin is a major component of coenzymes FAD and flavin mononuclotide (FMN) that play a key role in the metabolism of carbohydrates, amino acids, and lipids. Riboflavin is also intimately involved in the conversion of pyridoxine (vitamin B6) and folic acid (vitamin B9) into their coenzymes (2, 5). Humans and other mammals cannot synthesize riboflavin. However, this vitamin is found abundantly in milk, leafy green vegetables, and eggs. The dietary riboflavin is found primarily in the forms FAD and FMN. These coenzymes are hydrolyzed by intestinal luminal phosphatases before they can be absorbed (1, 3, 8). Transport of riboflavin has been extensively studied in human, rabbit, and rat small intestine. Riboflavin absorption in the mammalian small intestine occurs on the brush-border membrane (BBM) of the absorptive villus cells and is carrier mediated (9, 11–15). The role of Na1 dependency for riboflavin uptake in the small intestine is not completely clear, because BBM vesicle studies suggest no Na1 dependency, whereas intact tissue studies suggest a role for Na1. Taken together, these findings may suggest a secondary role for Na1 dependency in riboflavin small intestinal absorption compared with a more direct dependency necessary for Na1-nutrient cotransport processes such as Na1glucose cotransport (9, 13–15). An equally important source of riboflavin is bacterially synthesized riboflavin in the colon. Colonic flora synthesize a considerable amount of this vitamin and which in the colon is available for absorption in the free form (6, 7). Although the small intestinal assimilation of riboflavin appears to be regulated by the amount of the vitamin ingested (18), the colonic absorption is more dependent on the type of diet ingested. The colonic bacteria appear to produce more riboflavin when a more fiber-based diet (e.g., green leafy vegetables) is ingested compared with a meat-based diet. Thus with the former type of diet there is more of the vitamin for the colonic epithelium to absorb (6). The wide availability of riboflavin in food sources and the redundancy of intestinal absorption of this vitamin may point to its importance for the overall well-being of the organism. Indeed, deficiency of riboflavin results in a variety of pathophysiological states. Vitamin B2 deficiency is characterized by glossitis, cheilosis, angular stomatitis, seborrhea-like dermatitis, pruritus, photophobia, visual impairment, growth retardation, alopecia, and degenerative changes of the nervous system (2, 4, 5, 10). Thus better understanding of the intestinal assimilation of riboflavin is essential to prevent the wide range of disease entities associated with its deficiency. However, until recently very little was known about the cellular regulation of riboflavin transport. This was chiefly owing to the lack of suitable in vitro cell culture systems to study the transport of this vitamin. Recently, Said’s group in a series of studies has elegantly detailed the cellular mechanism of regulation of riboflavin transport in the colon. In one study using Caco-2 cells they demonstrated that riboflavin uptake is carrier mediated, Na1 independent, and inhibitable by cation exchange (e.g., amiloride) but not anion exchange inhibitors (e.g., stilbene derivatives), furosemide, or probenecid. Further, extracellular substrate concentration appeared to regulate the transporter by increasing the BBM transporter numbers (17). Whether this increase in transporter numbers is secondary to altered membrane trafficking and/or transcriptional changes of the riboflavin transporter has yet to be deciphered. Said et al. then demonstrated that protein kinase A (PKA), but not protein kinase C regulates the riboflavin transporter in Caco-2 cells. Increasing intracellular cAMP levels inhibited the uptake of riboflavin in these cells. The mechanism of PKA-mediated inhibition was not secondary to a decrease in the synthesis or membrane trafficking of the riboflavin transporter, but most likely secondary to a decrease in the activity of the transporter (16). Am. J. Physiol. Cell Physiol. 278: C268–C269, 2000