The effects of nitrous oxide on cobalamins, folates, and on related events

The anaesthetic gas nitrous oxide (N2O), when inhaled for longer than 6 hr, produces megaloblastic anemia in man. Longer term inhalation, as in addicts, produces a syndrome similar to that due to B12 neuropathy, and long term exposure to low concentrations results in an increased abortion rate and neuropathy, particularly in dental personnel. N2O acts by oxidizing vitamin B12 from the active reduced cob[I]alamin form to the inactive cob[III]alamin form. In turn, this inactivates the enzyme methionine synthetase which requires both B12 and folate as cofactors. In the rat, hepatic methionine synthetase is completely inactivated after 3 hr exposure to a mixture of equal parts of N2O/O2. There is an impared uptake of folate analogues by the liver so that the plasma folate level rises and thereafter there is a considerable loss of folate into the urine. Hepatic folate concentration falls to 25% within 10 days of N2O exposure. There is a failure to synthesize folate polyglutamate (the active folate coenzyme) from all other than formyltetrahydrofolate. As oxidization of the methyl of methionine is an important source of formyl, the failure of methionine synthesis in turn appears to lead to the failure in supply of formate and, hence, a lack of the formylfolate substrate.