Intestinal Absorption and Transport into Somatic Cells

At physiologic pH, the carboxylate group of biotin is negatively charged. Thus, biotin is at least modestly water-soluble and requires a transporter to cross cell membranes such as enterocytes for intestinal absorption, somatic cells for utilization, and renal tubule cells for reclamation from the glomeru-lar filtrate. In intact intestinal preparations such as loops and everted gut sacks, biotin transport exhibits two components. One component is saturable at a km of approximately 10 mM biotin; the other is not saturable even at very large concentrations of biotin. This observation is consistent with passive diffusion. Absorption of biocytin, the biotinyl-lysine product of intraluminal protein digestion, is inefficient relative to biotin, suggesting that biotinidase releases biotin from dietary protein. The transporter is present in the intestinal brush border membrane. Transport is highly structurally specific, temperature dependent, Na+ coupled, and electroneutral. In the presence of a sodium ion gradient, biotin transport occurs against a concentration gradient.

In rats, biotin transport is upregulated with maturation and by biotin deficiency. Although carrier-mediated transport of biotin is most active in the proximal small bowel of the rat, the absorption of biotin from the proximal colon is still significant, supporting the potential nutritional significance of biotin synthesized and released by enteric flora. Clinical studies have provided evidence that biotin is absorbed from the human colon, but studies in swine indicate that absorption of biotin from the hindgut is much less efficient than from the upper intestine; furthermore, biotin synthesized by enteric flora is probably not present at a location or in a form in which bacterial biotin contributes importantly to absorbed biotin. Exit of biotin from the enterocyte (i.e., transport across the basolateral membrane) is also carrier mediated. However, basolateral transport is independent of Na+, elec-trogenic, and does not accumulate biotin against a concentration gradient.

Based on a study in which biotin was administered orally in pharmacologic amounts, the bioavailability of biotin is approximately 100%. Thus, the pharmacologic doses of biotin given to treat biotin-dependent inborn errors of metabolism are likely to be well absorbed. Moreover, the finding of high bioavailabil-ity of biotin at pharmacologic doses provides at least some basis for predicting that bioavailability will also be high at the physiologic doses at which the biotin transporter mediates uptake.

Studies of a variety of hepatic cell lines indicate that uptake of free biotin is similar to intestinal uptake; transport is mediated by a specialized carrier system that is Na+ dependent, electroneutral, and structurally specific for a free carboxyl group. At large concentrations, transport is mediated by diffusion. Metabolic trapping (e.g., biotin bound cova-lently to intracellular proteins) is also important. After entering the hepatocyte, biotin diffuses into the mitochondria via a pH-dependent process.

Two biotin transporters have been described: a multivitamin transporter present in many tissues and a biotin transporter identified in human lymphocytes. In 1997, Prasad and coworkers discovered a Na+-coupled, saturable, structurally specific transporter present in human placental choriocarcinoma cells that can transport pantothenic acid, lipoic acid, and biotin. This sodium-dependent multivitamin transporter has been named SMVT and is widely expressed in human tissues. Studies by Said and coworkers using RNA interference specific for SMVT provide strong evidence that biotin uptake by Caco-2 and HepG2 cells occurs via SMVT; thus, intestinal absorption and hepatic uptake are likely mediated by SMVT. The biotin transporter identified in lymphocytes is also Na+ coupled, saturable, and structurally specific. Studies by Zempleni and coworkers provide evidence in favor of mono-carboxylate transporter-1 as the lymphocyte biotin transporter.

A child with biotin dependence due to a defect in the lymphocyte biotin transporter has been reported. The SMVT gene sequence was normal. The investigators speculate that lymphocyte biotin transporter is expressed in other tissues and mediates some critical aspect of biotin homeostasis.

Ozand and collaborators described several patients in Saudi Arabia with biotin-responsive basal ganglia disease. Symptoms include confusion, lethargy, vomiting, seizures, dystonia, dysarthria, dysphagia, seventh nerve paralysis, quadriparesis, ataxia, hypertension, chorea, and coma. A defect in the biotin transporter system across the blood-brain barrier was postulated. Additional work by Gusella and coworkers has suggested that SLC19A3 may be responsible for the reported defect.

The relationship of these putative biotin transporters to each other and their relative roles in intestinal absorption, transport into various organs, and renal reclamation remain to be elucidated.

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