Fig. 1.

A summary of the biochemical reactions involving folate and vitamin B₁₂ inside an oligodendrocyte and proposed inhibition of myelin production by co-administration of methotrexate (MTX) and drugs affecting vitamin B₁₂. Abbreviations: 5-MTHF (5-methyltetrahydrofolate, levomefolic acid), MB ₁₂ (methyl B₁₂), THF (tetrahydrofolate, tetrahydrofolic acid), 5,10-MTHF (5,10-methylene THF), DHF (dihydrofolate, dihydrofolic acid), DHFR (dihydrofolate reductase), MB ₁₂ (methyl-vitamin B₁₂), MTHFR (methylenetetrafolate reductase), MTX (methotrexate), met synthase (methionine synthase), SHMT (serine hydroxyl-methyltransferase). MTHF participates in the production of methionine from homocysteine by methionine synthase, catalyzed by MB₁₂ and zinc, creating THF and methionine. THF participates in the production of purines and pyrimidines for DNA synthesis. Methionine is a vital amino acid involved in myelin production via its conversion to S-adenosyl methionine (SAM). SAM is involved in the methylation of many proteins and intermediates ultimately involved in myelin production, such as phosphatidylcholine, which is important in the production of sphingomyelin, a major component of the myelin sheath. Homocysteine can be converted to homocysteic acid and homocysteine sulfinic acid which are excitotoxic glutamate analogues acting at the N-methyl-d-aspartate (NMDA) receptor, which may be a factor in acute methotrexate-induced neurotoxicity. Methotrexate inhibits the function of DHFR, preventing the conversion of DHF to MTHF. Active vitamin B₁₂ contains reduced cobalt (Co⁺), but nitrous oxide (N₂O) produces irreversible oxidation to Co⁺⁺ and Co⁺⁺⁺, rendering vitamin B₁₂ inactive. Any simultaneous compromise of folate and vitamin B₁₂ via co-administration of methotrexate and agents known to deplete active vitamin B₁₂, such as N₂O could result in increased homocysteine and reduced methionine levels both of which may contribute to the neurotoxic effects of methotrexate treatment. Other as yet unidentified compounds may also reduce bioavailable vitamin B₁₂ levels. Blue arrows indicate proposed increase or reduction in various relevant pathway metabolites