Nitrous oxide has multiple deleterious effects on cobalamin metabolism and causes decreases in activities of both mammalian cobalamin-dependent enzymes in rats

H. Kondo, Molly Osborne, J. F. Kolhouse, M. J. Binder, E. R. Podell, C. S. Utley, R. S. Abrams, R. H. Allen

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Abstract

In man, use of the general anesthetic nitrous oxide, N 2O, is associated with hematologic and neurologic abnormalities that mimic those seen in cobalamin (Cbl, vitamin B 12) deficiency. We have measured a number of aspects of Cbl metabolism in rats exposed to various concentrations of N 2O for various periods of time. As little as 2% N 2O given for 15 h resulted in 30% inhibition of methionine synthetase (MS) in rat liver. With 50% N 2O, inhibition of 70% occurred within 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 N 2O was stopped. Studies employing rats previously injected with [ 57Co]Cbl showed that N 2O 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. N 2O also caused the hepatic content of CH 3-[ 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 N 2O, but not in control animals. When rats were exposed to 50% N 2O 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 N 2O causes multiple defects in Cbl metabolism that include the following: (a) rapid inhibition of MS activity with a slow recovery when N 2O is stopped; (b) displacement of Cbl from MS; (c) decreased CH 3-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.

Original languageEnglish (US)
Pages (from-to)1270-1283
Number of pages14
JournalJournal of Clinical Investigation
Volume67
Issue number5
StatePublished - 1981
Externally publishedYes

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5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
Nitrous Oxide
Vitamin B 12
Enzymes
Methylmalonyl-CoA Mutase
Liver
Nervous System Malformations
Vitamin B 12 Deficiency
Paper Chromatography
General Anesthetics

ASJC Scopus subject areas

  • Medicine(all)

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Nitrous oxide has multiple deleterious effects on cobalamin metabolism and causes decreases in activities of both mammalian cobalamin-dependent enzymes in rats. / Kondo, H.; Osborne, Molly; Kolhouse, J. F.; Binder, M. J.; Podell, E. R.; Utley, C. S.; Abrams, R. S.; Allen, R. H.

In: Journal of Clinical Investigation, Vol. 67, No. 5, 1981, p. 1270-1283.

Research output: Contribution to journalArticle

Kondo, H. ; Osborne, Molly ; Kolhouse, J. F. ; Binder, M. J. ; Podell, E. R. ; Utley, C. S. ; Abrams, R. S. ; Allen, R. H. / Nitrous oxide has multiple deleterious effects on cobalamin metabolism and causes decreases in activities of both mammalian cobalamin-dependent enzymes in rats. In: Journal of Clinical Investigation. 1981 ; Vol. 67, No. 5. pp. 1270-1283.
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abstract = "In man, use of the general anesthetic nitrous oxide, N 2O, is associated with hematologic and neurologic abnormalities that mimic those seen in cobalamin (Cbl, vitamin B 12) deficiency. We have measured a number of aspects of Cbl metabolism in rats exposed to various concentrations of N 2O for various periods of time. As little as 2{\%} N 2O given for 15 h resulted in 30{\%} inhibition of methionine synthetase (MS) in rat liver. With 50{\%} N 2O, inhibition of 70{\%} occurred within 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 N 2O was stopped. Studies employing rats previously injected with [ 57Co]Cbl showed that N 2O 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. N 2O also caused the hepatic content of CH 3-[ 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 N 2O, but not in control animals. When rats were exposed to 50{\%} N 2O 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 N 2O causes multiple defects in Cbl metabolism that include the following: (a) rapid inhibition of MS activity with a slow recovery when N 2O is stopped; (b) displacement of Cbl from MS; (c) decreased CH 3-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.",
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T1 - Nitrous oxide has multiple deleterious effects on cobalamin metabolism and causes decreases in activities of both mammalian cobalamin-dependent enzymes in rats

AU - Kondo, H.

AU - Osborne, Molly

AU - Kolhouse, J. F.

AU - Binder, M. J.

AU - Podell, E. R.

AU - Utley, C. S.

AU - Abrams, R. S.

AU - Allen, R. H.

PY - 1981

Y1 - 1981

N2 - In man, use of the general anesthetic nitrous oxide, N 2O, is associated with hematologic and neurologic abnormalities that mimic those seen in cobalamin (Cbl, vitamin B 12) deficiency. We have measured a number of aspects of Cbl metabolism in rats exposed to various concentrations of N 2O for various periods of time. As little as 2% N 2O given for 15 h resulted in 30% inhibition of methionine synthetase (MS) in rat liver. With 50% N 2O, inhibition of 70% occurred within 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 N 2O was stopped. Studies employing rats previously injected with [ 57Co]Cbl showed that N 2O 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. N 2O also caused the hepatic content of CH 3-[ 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 N 2O, but not in control animals. When rats were exposed to 50% N 2O 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 N 2O causes multiple defects in Cbl metabolism that include the following: (a) rapid inhibition of MS activity with a slow recovery when N 2O is stopped; (b) displacement of Cbl from MS; (c) decreased CH 3-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.

AB - In man, use of the general anesthetic nitrous oxide, N 2O, is associated with hematologic and neurologic abnormalities that mimic those seen in cobalamin (Cbl, vitamin B 12) deficiency. We have measured a number of aspects of Cbl metabolism in rats exposed to various concentrations of N 2O for various periods of time. As little as 2% N 2O given for 15 h resulted in 30% inhibition of methionine synthetase (MS) in rat liver. With 50% N 2O, inhibition of 70% occurred within 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 N 2O was stopped. Studies employing rats previously injected with [ 57Co]Cbl showed that N 2O 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. N 2O also caused the hepatic content of CH 3-[ 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 N 2O, but not in control animals. When rats were exposed to 50% N 2O 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 N 2O causes multiple defects in Cbl metabolism that include the following: (a) rapid inhibition of MS activity with a slow recovery when N 2O is stopped; (b) displacement of Cbl from MS; (c) decreased CH 3-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.

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