The sodium-dependent multivitamin transporter transports biotin, pantothenic acid and lipoate (Prasad et al. 1997). The three vitamins competitively inhibit transport of each other. Lipoate inhibits the transport of biotin and pantothenic acid (Prasad et al. 1998). Biotin is taken in microgram quanties while lipoic acid is taken in 600 milligram and higher quantites. What is more lipoate is synthesized on proteins whereby there is no need for free lipoic acid. All supplemental lipoic acid would be doing is blocking the transport of biotin and pantothenic acid.
Biotinis synthesized by by micororganisms in the gut. Pantothenic acid is also synthesized by microorganisms in the gut. Biotin and pantohenic acid are involved in bipolar depression. See the page on Bipolar depression. Changes is gut microbiota could, by affecting biotin synthesis and pantothenic acid synthesis and have an effect on bipolar depression.
Hypoxia-inducible factor 1alpha (HIF-1α) induces transcription of thiamine transporter 2 by binding to the promoter of thiamine transporter 2. HIF-1α and hypoxia-inducible factor 2alpha bind to the same hypoxia responsive elements is promoters of hypoxia regulated genes. Hypoxia-inducible factor-2alpha is also called endothelial PAS domain-containing protein 1 (EPAS1).
EPAS1 mRNA has an iron response element in the 5′ untranslated region. Wheniron regulatory proteins(IRPs) bind to an iron response elements in the 5′ untranslated region of mRNA transcripts mRNA transcripts are destabilized reducing translation of iron responsive genes.
EPAS1 could like HIF-1α bind to promoters of the gene for thiamine transporter 2. However increased activity of IRP1 could destabilize EPAS1 mRNA transcripts reducing transcription of thiamine transporter 2 in response to hypoxia.
Neuropathy could result from increased activity of IRP1. With increased activity of IRP1 there could be low levels of EPAS1. Overtime with hypoxia not inducing thiamine transporter 2 the gene for thiamine tranpor 2 could become hypermethylated. Taking only RDA amounts of thiamine is then no longer sufficuent.
For neuropathy a combination of iron from carbonyl iron, thiamine and biotin could be of assistance.Irondecreases IRP1 activity which would stabilize mRNA transcipts of EPAS1 so thiamine transporter 2 can be induced by EPAS1. Thiamine and biotin supplementation can treat mutations in thiamine transporter 2.
When biotin is supplemented biotin is supplemented three times a day while pantothenic acid is supplemented once a day also but away from biotin. Intestinal absorption of biotin is via the sodium-dependent multivitamin transporter (SMVT) where the SMVT also transports pantothenate. High dosages of pantothenic acid taken at the same time as biotin could inhibit transport of biotin. Biotinylation of the SMVT locus inhibits transcription of the SMVT gene so biotin cannot be taken at the same time as pantothenic acid.
The SMVTalso transports lipoic acid. Supplementing with lipoic acid must be avoided as lipoic acid supplementation would competitively inhibit the transport of biotin and pantothenic acid by the SMVT.
There is no genetic defect nor is there a systematic thiamine deficiency where there is neuropathy arises due to high levels of IRP1. Only some thiamine transporter 2 genes are hypermethylated. Localized thiamine deficiencies do not have the symptoms of generalized thiamine deficiences, however, one of the symptoms of localized thiamine deficiencies could be neuropathy.
Synthesis of thiamine diphosphate by thiamine pyrophosphokinase requires ATP. Creatine buffers ATP. Creatine taken four times a day can be of asssistance in the treatment of neuropathy due to high levels of IRP1 as long as creatine is taken with iron from carbonyl iron, thiamine and biotin.
Vitamin B6 will worsen a neuropathy due to increased levels of IRP1 likely due to an effect on glutamic–pyruvic transaminase and serine-pyruvate transaminase which can not be supported due to dysregulation of aconitase 1 in the TCA cycle. Supplemental vitamin B6 could be of assistance given iron from carbonyl iron is supplemented.
Supplemental carbonyl iron, thiamine, biotin and pantothenic acid could be a more effective treatment for a lot of cases of neuropathy where supplemental vitamin B6 could also be assistance. Supplements and drinks on the list of ‘too be avoided supplements and drinks’ on the Treatment Page would have to be avoided.
In terms of alternative and complimentary medicine 5-MTHF, alpha lipoic acid, folate and N acetyl cysteine are mainline treatments for depression.
There are lots of grounds to think these supplements could be very unsafe. Lipoic acid shares the same transporterwith biotin and pantothentic acid. Lipoate inhibits the transport of pantothenic acid and biotin. The body uses miniscule quantities of biotin. 300 milligrams of lipoic acid twice a day could have a large negative affect on biotin transport. Lipoic acid does not work in bipolar depressionwhich is not suprising, See the page on Bipolar Depression.
N-acetyl cysteine is associated with musculoskeletal adverse side effects. These musculoskeletal adverse side effects are almost totally impossible to get rid of and can be horrendous. Clincal trials are usually about 6 weeks long but musculoskeletal effects accumulate over time and can persist long after N-acetyl cysteine is stopped.
There are no grounds whatsover to hold than S-adenosyl methionine taken long term would not affect DNA methylation and histone methylation. Abberrant DNA methylation is associated with cancer, aging and mental illnesses. Minimally an explantion as to why greatly increasing S-adenosyl-l-methionine levels does not affect DNA and histone methylation long term has to be given but no explanatiton is provided.
5-methyltetrahydrofolateinhibts glycine-N-methyltransferase which degrades S-adenosyl methionine. With 5-methyltetrahydrofolate supplementation S-adenosyl methionine levels would again be expected to greatly increase with again unknown consequences to DNA methylation and histone methylation. No consequences would be very surprising. Despite great early enthusiasm folic acid supplementation has been a bust in the prevention of a range of illnesses associated with high homocysteine levels.
What is it about these supplements that makes them so attractive? One very definitely notices these supplements when one takes them.
Pyruvate carboxylaseis a biotin-dependent enzyme involved in gluconeogenesis and lipogenesis, in the biosynthesis of neurotransmitters, and in glucose-induced insulin secretion by pancreatic islets. Pyruvate carboxylase is a key to beta cell adaptationto insulin resistance where pyruvate carboxylase reduction can lead to beta cell failure. In Agouti-K micereduction of pyruvate carboxylase in pancreatic islets could play a role in the development of Type 2 diabetes.
Biotin deficiencies both by decreasing metabolism of branched-chain amino acids and decreasing activity of pyruvate carboxylase could lead to the development of metabolic syndrome in humans. Both biotin and pantothenate would have to be taken to treat metabolic syndrome where biotin would be taken three times a day and pantothenic acid taken once a day away from biotin. Both biotin and pantothenate are transportedby the the sodium-dependent multivitamin transporter (SMVT). Pantothenic acid taken alone could competitively inhibit transport of biotin by the SMVT while biotin taken alone could decrease transport of pantothenic acid by biotinylation of histones at the SMVT locus.
Elevated circulating levelsof branched-chain amino acids have been associated with insulin resistance where decreased degradation of branched-chain amino acids could be what is leading to elevated circulating levels of branched-chain amino acids. Metabolic syndrome is associated with insulin resistance.
Insulin resistance is present in 52% of individuals with bipolar disorder. Insulin resistance develops is brains of individuals with Alzheimer’s disease. In China in individuals with schizophrenia the prevalence of insulin resistance is 37.2% Both disease processes and drugs used to treat these illnesses could increase insulin resistance in theses illnesses. A commonality among these illnesses could be dysregulation of the sodium-dependent multivitamin transporter both by disease processes and drugs used to treat these illnesses.
The sodium-dependent multivitamin transporter transports both biotin and pantothenate. Pantothenate is needed to synthesize coenzyme A which is closely tied to the actions of biotin-dependent enzymes. Biotinylationof the sodium-dependent transporter reduces transport by the sodium-dependent multivitamin transporter. High levels of biotin could decrease transport of pantothenate by the sodium-dependent multivitamin transporter. A combination of pantothenic acid and biotin where 500 mg. of pantothenic acid is taken once a day away from supplemental biotin and 5 mg of biotin is taken three times a day could word work better in controlling hyperglycemia than biotin alone.
The sodium-dependent multivitamin transporter (SMVT) also transports iodide. How important the SMVT is for iodide transport is not clear. Supplementing with biotin and pantothenic acid, however, could competitively block the transport of iodide by the SMVT. There is another transporter of of iodide, the sodium/iodide cotransporter, (SLC5A5) which is largely expressed in the thyroid. The SMVTis expressed in the digestive tract.
Acetyl-CoA carboxylase is a biotin-dependent enzyme that catalyzes the irreversible carboxylation of acetyl-CoA to produce malonyl-CoA. Malonyl-CoA inhibits the rate-limiting step in beta-oxidation of fatty acids. Malonyl-CoA inhibits fatty acids from associating with carnitine by regulating the enzyme carnitine acyltransferase.
Biotin supplementation would then both inhibit beta-oxidation and assist with chain elongation in fatty acid biosynthesis.
I have been arguing that increases is beta-oxidation that result from increased intakes of polyphenols can lead to difficulties in schizophrenia. Given the dual functions of malonyl-CoA in inhibiting beta-oxidation and assisting with fatty acid elongation if there is excessive beta-oxidation there could be difficulties in fatty acid elongation. Supplemental biotin would decrease beta-oxidation and increase fatty acid elongation which would be headed in the right direction. Biotin would not be supplemented at the same time as pantothenic acid as pantothenic acid is a competitive inhibitor of biotin transport.