Biotin, a member of the B-vitamin family, is an essential nutrient in human nutrition. It is involved in the biosynthesis of fatty acids, gluconeogenesis, energy production, the metabolism of the branched-chain amino acids (L-leucine, L-isoleucine, L-valine) and the de novo synthesis of purine nucleotides. Recent research indicates that biotin plays a role in gene expression, both at the transcriptional and translational levels, and that it may also play a role in DNA replication.
Biotin is widely distributed in natural foodstuffs. However, the absolute amounts of biotin in foodstuffs is relatively low when compared with the other B vitamins. Some of the better food sources of biotin, are egg yolk, liver, kidney, pancreas, milk, soya and barley. Brewer's yeast or Saccharomyces cerevisiae (see Brewer's Yeast), which is used as a nutritional supplement, is one of the richest sources of biotin, as well as the other B vitamins. Royal jelly, also used as a nutritional supplement (see Royal Jelly), is another rich source of biotin. Mammals and many plant species are unable to synthesize biotin. Biotin is synthesized by bacteria, yeast and other fungi, algae and certain plant species. In fact, the microflora of the human large intestine appear to contribute to the biotin requirements of the body.
The first demonstration of biotin deficiency in animals was observed in animals fed raw egg white. Rats fed egg white protein were found to develop dermatitis, hair loss and neuromuscular dysfunction. This syndrome was called egg white injury and was discovered to be caused by a glycoprotein found in egg white called avidin. It was subsequently found that egg white injury could be cured by a liver factor which was first called protective factor X and later determined to be biotin. Because biotin cured the skin disorder of egg white injury it was called vitamin H. H is for haut, the German word for skin. Avidin causes egg white injury because it binds very tightly to biotin, preventing its absorption. This is only true for native avidin, which is resistant to hydrolysis by proteolytic enzymes. When egg white is cooked, avidin is denatured and denatured avidin is digested by proteolytic enzymes.
Although clinical biotin deficiency in humans is rare, it does occur. Prolonged consumption of raw egg white, long-term total parenteral nutrition without biotin supplementation and malabsorption syndromes, such as short-gut syndrome, have resulted in biotin deficiency states. The symptoms and signs of biotin deficiency, include a generalized erythematous scaly skin eruption, alopecia, conjunctivitis and neurological abnormalities. The rash may be distributed around the eyes, nose, mouth, ears and perineal orifices. The facial appearance associated with the deficiency, with the rash around the eyes, nose and mouth along with an unusual distribution of facial fat, is called biotin deficiency facies. In biotin deficient infants, the neurological findings are hypotonia, lethargy and developmental delay. In adults, the neurological findings are lethargy, depression, hallucinations and paresthesias of the extremities. Marginal biotin status may occur under certain conditions, e.g., during the first trimester of pregnancy, and it is thought that this situation may be teratogenic. Functional biotin deficiency occurs in certain genetic disorders. These will be discussed below.
Biotin is the coenzyme for four carboxylases. Acetyl coenzyme A (CoA) carboxylase, found in both the mitochondria and cytosol, catalyzes the carboxylation of acetyl-CoA to malonyl-CoA. Malonyl-CoA is the immediate precursor of 14 of the 16 carbon atoms of the fatty acid palmitic acid. It is also the immediate precursor of all of the fatty acids up to palmitic acid. Further, the reaction catalyzed by acetyl-CoA carboxylase, a complex reaction, is the primary regulatory, or rate-limiting, step in the biosynthesis of fatty acids. Pyruvate carboxylase, which is located in the mitochondria, catalyzes the carboxylation of pyruvate to form oxaloacetate. Oxaloacetate can be metabolized in the tricarboxylic acid cycle or it can be converted to glucose in the liver and kidney and other tissues that are involved in gluconeogenesis. The formation of oxaloacetate from pyruvate is known as an anaplerotic reaction. Anaplerotic is from the Greek word anaplerosis, meaning filling up or restoration. The pyruvate carboxylate reaction is the principal reaction which replenishes tricarboxylic acid cycle intermediates. Methylcrotonyl-CoA carboxylase, also located in the mitochondria, is involved in the metabolism of L-leucine, while the mitochondrial enzyme propionyl-CoA carboxylase is involved in the metabolism of L-isoleucine and L-valine, as well as L-threonine and L-methionine.
All four of the carboxylase enzymes, which use bicarbonate as their one-carbon substrate, share a common biochemical mechanism. In all four carboxylases, biotin is covalently linked by an amide bond between the carboxyl group of the valeric side chain of biotin and an epsilon-amino group of a specific lysyl residue in the apocarboxylase. The enzyme that catalyzes the formation of the covalent bond is called holocarboxylase synthetase. Biotin is recycled by the enzyme biotinidase. Biotinidase, an hydrolase, functions to recycle biotin by cleaving biocytin (epsilon-N-biotinyl-L-lysine), or short-chain oligopeptides containing biotin-linked lysyl residues, products of the normal breakdown of the holocarboxylases, to free biotin. Biotinidase is also thought to play a critical role in the release of biotin from biotin-containing dietary proteins. Recently, biotinidase has been found to have biotinyl-transferase activity. All five classes of histones are selectively biotinylated via the biotinyl-transferase activity of biotinidase. It is thought that biotinylation of histones is involved in the regulation of gene transcription and may also play a role in the packaging of DNA. Interestingly, biotinylation is an important technique in molecular biology. Biotin can be covalently linked to both proteins and nucleic acids, and is used as a label in many molecular biology and biochemistry technologies.
Certain inborn errors of metabolism result in functional biotin deficiency. These disorders, include multiple carboxylase deficiency, holocarboxylase synthetase deficiency, biotinidase deficiency and propionic-CoA carboxylase deficiency. Those with these disorders require much greater cellular biotin levels than normal in order to activate these biotin-dependent enzymes. Biotinidase deficiency is the most common cause of late-onset multiple carboxylase deficiency. Features of late-onset multiple carboxylase deficiency, include skin rash, alopecia, seizures, hypotonia, ataxia, hearing loss, optic atrophy, developmental delay, immune deficiency and recurrent infections. Coma and death may occur if the disorder is not treated. The treatment is high-dose biotin, which results in pronounced, rapid clinical and biochemical improvement. Holocarboxylase deficiency is the most common form of multiple carboxylase deficiency in neonates. Features of neonatal multiple carboxylase deficiency, include lethargy, hypotonia, vomiting, alopecia, lactic acidosis, keratoconjunctivitis, perioral erosions and seizures. Again, the treatment is high-dose biotin, which may completely reverse the symptoms and signs of the disorder. There is a relatively high incidence or propionyl-CoA carboxylase deficiency among the Inuits of Greenland. Those with this deficiency may present early in life with a severe, often fatal metabolic acidosis, hyperglycinemia and hyperammonemia. The only known treatment for this disorder is high-dose biotin. All of the above inborn errors of metabolism are referred to as biotin-responsive disorders.
Biotin is a bicyclic compound. The tetrahydrothiophene ring contains sulfur and has a valeric acid side chain. The second ring contains a ureido group. Eight stereoisomers of biotin exist. However, only one is found naturally, and it is the only one that is enzymatically active. The natural stereoisomer of biotin is called d-(++)-biotin or just biotin. In addition to being known as vitamin H, biotin is also known as hexahydro-2-oxo-1H-thieno[3,4-d]imidazole-4-pentanoic acid; cis -5-(hexahydro-2-oxo-1H-thieno[3,4-d]imidazol-4-yl)valeric acid; cis -tetrahydro-2-oxothieno[3,4-d]imidazoline-4-valeric acid; cis -hexahydro-2-oxo-1H-thieno[3,4]imidazole-4-valeric acid; coenzyme R and bios IIb. Its molecular formula is C10H16N2O3S and its molecular weight is 244.31 daltons. Biocytin or epsilon-N-biotinyl-L-lysine is a naturally occurring complex of biotin which has approximately the same biochemical activity as biotin.
Actions & Pharmacology
Biotin is used for the treatment of biotin-responsive inborn errors of metabolism. It has putative glucose tolerance-modulating activity. It may also have activity in the management of brittle fingernails and the uncombable hair syndrome. There is some evidence that it may have antioxidant activity.
Mechanism of Action
Holocarboxylase synthetase catalyzes the biotinylation of the four biotin-dependent carboxylases in humans. Holocarboxylase synthetase deficiency is the most common cause of neonatal multiple carboxylase deficiency. Biotinidase catalyzes the recycling of biotin, among other reactions. Biotinidase deficiency is the most common cause of late-onset multiple carboxylase deficiency. Cellular biotin concentrations higher than are normally present, are required to activate the mutant holocarboxylase synthetase and biotinidase enzymes. Biotin does not bind to the mutant enzymes as strongly as it does to non-mutant enzymes and therefore, greater amounts of biotin are required for their activation. Biotin may also play a role in the regulation of the transcription of holocarboxylase synthetase.
Biotin supplementation has been found to improve glucose tolerance and decrease insulin resistance in a diabetic mouse model. It has also been found to influence hepatic glucokinase expression both at the transcriptional and translational levels in cell culture. More recently, biotin has been shown to affect pancreatic islet glucokinase activity and expression and insulin secretion in cultured rat islet cells. Glucokinase has a central regulatory role in glucose metabolism. The results of above studies suggest that the administration of supplementary biotin may improve the metabolism and/or utilization of glucose in those with type 2 diabetes mellitus. Clinical trials are needed.
Some studies have found that high doses of biotin are helpful in the management of brittle fingernails in women. The rationale to use biotin for this condition came from the finding that pathologic hoof changes in horses and swine can be treated with oral biotin. The mechanism of the possible effect of biotin in the management of brittle fingernails is not known. Biotin deficiency does cause skin changes. However, the subjects studied were not biotin deficient.
The uncombable hair syndrome, also known as spun-glass hair and cheveux incoiffables, is a rare congenital disorder. It is characterized by a longitudinal grooving of the hair shaft resulting in a triangular cross section (pili trianguli et canaliculi). There is a report of biotin reversing scaling, hair loss, hair fragility, and uncombability in a two-year old boy with the syndrome. The hair remained combable even after one year. The mechanism of action of biotin in this condition is not known. Perhaps some cases of uncombable hair syndrome are biotin-responsive. The uncombable hair syndrome should not be confused with cowlicks, localized patches of hair that will not comb down. The cowlick is not a forme fruste of the uncombable hair syndrome, nor is there any evidence that biotin has any effect on cowlicks.
Biotin has been found to inhibit the generation of reactive oxygen species, including superoxide anions, by neutrophils, in vitro. The mechanism of this antioxidant effect is unknown. Biotin does not appear to scavenge superoxide anions.
The intestine is exposed to biotin from a few sources: the diet, biotin supplements and biotin synthesized by bacteria in the large intestine. Dietary biotin exists in free and protein-bound forms. Protein-bound biotin is digested by proteases and peptidases to biotin-containing oligopeptides and biocytin (epsilon-N-biotinyl-L-lysine). Biocytin and the biotin-containing oligopeptides are converted to biotin via the enzyme biotinidase. Biotin—both dietary-derived biotin and supplementary biotin—is efficiently absorbed from the small intestine. At doses of biotin derived from food, biotin appears to be transported into enterocytes by a sodium-dependent carrier. At higher doses of biotin, absorption appears to occur by passive diffusion. Absorption of the biotin produced by the colonic microflora, appears to occur by a carrier mediated process in the proximal large intestine.
Biotin is transported to the liver via the portal circulation and by the systemic circulation, to the other tissues of the body. Biotin appears to be transported in the serum in both bound and unbound forms. Uptake of biotin by cells appears to occur by both a sodium-dependent carrier process and by passive diffusion. Transport of biotin across the blood-brain barrier appears to occur by a saturable transport mechanism. Placental transport of biotin appears to occur by a passive process. Within cells, the carboxylases (pyruvate carboxylase, acetyl-CoA carboxylase, 3-methylcrotonyl-CoA carboxylase, propionyl-CoA carboxylase) are biotinylated via holocarboxylase synthetase. Biotin and apocarboxylases are the substrates. ATP and magnesium also participate in the reaction. Biotin is recycled from the holocarboxylases via the action of proteolytic enzymes and biotinidase. Biotin is catabolized to a number of different metabolites, including bisnorbiotin, biotin sulfoxide, biotin sulfone, bisonorbiotin methylketone and tetranorbiotin-1-sulfoxide. Biotin is excreted in the urine as biotin, bisnorbiotin, biotin sulfoxide, biotin sulfone, bisnorbiotin methyl ketone and tetranobiotin-1-sulfoxide.
Indications & Usage
Biotin is used to treat the biotin-responsive inborn errors of metabolism holocarboxylase synthetase deficiency and biotinidase deficiency. Holocarboxylase deficiency is the most common cause of neonatal multiple carboxylase deficiency. Biotinidase deficiency is the most common cause of late-onset multiple carboxylase deficiency.
Recent studies have revealed that even marginal biotin deficiency is teratogenic in many mammals. This is of special concern since there is also now data showing that marginal biotin deficiency occurs in a significant proportion of pregnant women. It is too early to recommend widespread biotin supplementation during pregnancy, but the use of this vitamin might be indicated in some pregnant women whose physicians advise its use. There is very preliminary evidence that supplemental biotin might improve disordered glucose metabolism and thus might be helpful in some cases of diabetes. It may also be indicated in some cases of those on total parenteral nutrition and in some with brittle nails. There is some dated evidence that biotin can favorably affect lipids. There is no evidence that it can restore hair growth except in some cases of biotin deficiency. Nor will it reverse graying of hair. There is some evidence, however, that it may help manage the ""uncombable hair syndrome,'' a rare condition seen in children. There is no evidence that biotin improves exercise performance.
Biotin is available in multivitamin and multivitamin/multimineral products as well as in single ingredient products. In single ingredient products, biotin is available as lozenges, tablets and capsules. Few prenatal vitamin/mineral formulas contain biotin. Those that do, typically contain biotin in doses of about 30 micrograms daily. Biotin is present in several combination products at doses of 30 to 60 micrograms daily. Intakes of biotin range from 30 to 1,000 micrograms/day.
The Food and Nutrition Board of the Institute of Medicine of the National Academy of Sciences has recommended the following Dietary Reference Intakes (DRI) for biotin:
|Children 1 through 3 years||8 micrograms/day 4 through 8 years||12 micrograms/day|
|Boys 9 through 13 years||20 micrograms/day 14 through 18 years||25 micrograms/day|
|Girls 9 through 13 years||20 micrograms/day 14 through 18 years||25 micrograms/day|
|Men 19 years and older||30 micrograms/day|
|Women 19 years and older||30 micrograms/day|
|Pregnancy 14 through 50 years||30 micrograms/day|
|Lactation 14 through 50 years||35 micrograms/day|
The optimal intake values for biotin are not known. Those receiving hemodialysis, peritoneal dialysis or who have genetic abnormalities of biotin-dependent enzymes, such as biotinidase deficiency, have increased requirements for biotin. There are probably other such situations.
The DV (Daily Value) for biotin, which is used for determining percentage of nutrient daily values on nutritional supplement and food labels, is 300 micrograms. This is based on the U.S. RDA for biotin.
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High incidence of propionic acidemia in Greenland is due to a prevalent mutation, 1540insCCC, in the gene for the beta-subunit of propionyl CoA carboxylase. Am J Hum Genet. 2000; 67:203-206.Reddi A, DeAngelis B, Frank O, et al. Biotin supplementation improves glucose and insulin tolerances in genetically diabetic KK mice. Life Sci. 1988; 42:1323-1330.Rodriguez Melendez R. [Importance of biotin metabolism]. [Article in Spanish]. Rev Invest Clin. 2000; 52:194-199.Sekiguchi T, Nagamine T. Inhibition of free radical generation by biotin. Biochem Pharmacol. 1994; 47:594-596.Shelley WB, Shelley ED. Uncombable hair syndrome: observations on response to biotin and occurrence in siblings with ectodermal dysplasia. J Am Acad Dermatol. 1985; 13:97-102.Sugita Y, Shirakawa H, Sugimoto R, et al. Effect of biotin treatment on hepatic gene expression in streptozotocin-induced diabetic rats. Biosci Biotechnol Biochem. 2008;72(5):1290-1298.Velazquez A, Baez TM, Gutierrez J, Rodriguez R. 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Research & Summary
Biotin deficiency has been shown to cause birth defects in several animal, including mammalian, species. The level of deficiency required to be teratogenic is marginal, insufficient to produce any of the typical cutaneous and behavioral manifestations of more pronounced deficiency. These findings, coupled with recent disclosures that marginal biotin deficiency occurs in a significant proportion of pregnant women, raises serious concern.
A recent analysis of data from a multivitamin supplementation study has led one research group to conclude that there is at least indirect evidence of teratogenicity due to marginal biotin deficiency in humans. Adding to the concern are further findings that biotin deficiency can occur spontaneously in normal human gestation, that biotin transport by the human placenta is mainly passive and that proliferating cells have increased biotin requirements.
More research is required before biotin can be recommended for pregnant women as an antiteratogen, but physicians may find it appropriate to recommend its use in individual cases.
There are some recent preliminary animal studies suggesting that biotin may help improve glucose metabolism in ways that might be beneficial in some with diabetes. In one experiment, biotin supplemented diabetic mice had, compared with controls, lowered post-prandial glucose levels, improved glucose tolerance and decreased insulin resistance. Similar results were obtained in another animal study, leading the researchers to conclude that biotin may be helpful to patients with non-insulin-dependent diabetes mellitus (type 2 diabetes mellitus).
It has been claimed that supplemental biotin can reverse loss and graying of hair. In fact, biotin and pantothenic acid are widely used in cosmetic hair products. Except in cases of frank biotin deficiency, there appears to be no basis for this claim. There is a report, however, that severe hair loss secondary to biotin deficiency occurs in some patients receiving total parenteral nutrition (TPN). Supplementation with 200 micrograms of biotin daily has resulted in gradual regrowth of healthy hair in some of these patients.
There is also a report that supplemental biotin can help tame ""uncombable hair syndrome'' characterized by hair loss, hair fragility and uncombability, a rare disorder of children.
Biotin reportedly benefits some with brittle nails, as well. Supplementation with biotin resulted in a significant thickening of nail plates in 63% of subjects in a Swiss study.
There is a dated (1980) report that 0.9 milligrams of biotin daily for 71 days significantly and favorably affected lipids in 40 subjects aged 30-60. This isolated report needs follow-up.
Contraindications, Precautions & Adverse Reactions
Biotin is contraindicated in those hypersensitive to any component of a biotin-containing product.
Pregnant women and nursing mothers should avoid supplemental doses of biotin greater than the adequate intakes (AI) recommended by the Food and Nutrition Board, unless higher doses are prescribed by their physicians. The AIs are 30 micrograms/day for pregnant women and 35 micrograms/day for nursing mothers.
The use of biotin for the treatment of a biotin-responsive medical conditions requires medical supervision.
There are no reports of adverse reactions associated with biotin supplementation in the literature.
Antibiotics: Antibiotic use may decrease the biotin contribution to the body made by the microflora of the large intestine.
Anticonvulsants (carbamazepine, phenytoin, phenobarbital, primidone): Carbamazepine, phenytoin and phenobarbital can accelerate biotin metabolism and may cause reduced biotin status. Long-term use of carbamazepine, phenytoin, phenobarbital and primidone has been associated with reduced plasma concentrations of biotin.
Pantothenic Acid: High-doses of pantothenic acid may inhibit the absorption of biotin produced by the microflora in the large intestine. Pantothenic acid and biotin appear to use the same uptake carrier in colonocytes.