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In man, use of the general anesthetic nitrous oxide, N2O, is associated with hematologic and neurologic abnormalities that mimic those seen in cobalamin (Cbl, vitamin B12) deficiency. We have measured a number of aspects of Cbl metabolism in rts exposed to various concentrations of N2O for various periods of time. As little as 2% N2O given for 15 h resulted in 30% inhibition of methionine synthetase (MS) in rat liver. With 50% N2O, inhibition of 70% occurred with 1 h and did not change during the next 48 h. Under these conditions, no inhibition of methylmalonyl-CoA mutase (MMCoAM) was observed. The recovery of MS activity was slow and was only 80% of control values 72 h after N2O was stopped. Studies employing rats previously injected with [57Co]Cbl showed that N2O displaced [57Co]Cbl from MS in a manner that temporally and quantitatively paralleled the loss of MS activity. Recovery of MS activity paralleled the reappearance of [57Co]Cbl on MS. N2O also caused the hepatic content of CH3-[57Co]Cbl to decrease by 20-60%. When [57Co]-Cbl was extracted from liver and analyzed by paper chromatography, [57Co]Cbl analogues were present (10-40% of total [57Co]Cbl) in rats exposed to N2O, but not in control animals. When rats were exposed to 50% N2O for 33 d, the total of endogenous Cbl and Cbl analogues in liver decreased to 35% of control values and endogenous Cbl decreased to 10% of control values. At this time, MS activity was 15% of control values and MMCoAM was only 26% of control values. We conclude that N2O causes multiple defects in Cbl metabolism that include the following: (a) rapid inhibition of MS activity with a slow recovery when N2O is stopped; (b) displacement of Cbl from MS; (c) decreased CH3-Cbl; (d) conversion of Cbl to Cbl analogues; (e) the gradual development of Cbl deficiency and (f) an eventual decrease in MMCoAM activity with a further decrease in MS activity.