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. When iron 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. Iron decreases 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 SMVT also 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.