Induction of a reversible block in murine CFU-C differentiation by exposure to nitrous oxide.
Patients subjected to prolonged exposure to nitrous oxide (N2O) often develop megaloblastic bone marrow changes. This toxicity is due to the N2O-mediated inactivation of cobalamin-dependent enzymes with resultant perturbations in cell metabolism. The effect of N2O on the behavior of murine colony-forming units-cytokine (CFU-C) in vitro was studied by incubating granulocyte/macrophage colony-stimulating factor (GM-CSF)-stimulated bone marrow cultures for 7 days in an atmosphere of either 5% CO2 in air or 50% N2O/5% CO2 in air. Exposure of bone marrow cells in agarose to N2O resulted in an approximately 50% reduction in colony formation when compared with cultures incubated in air. In contrast, when residual CFU-C numbers were determined in bone marrow liquid cultures after 7 days of incubation in the presence of GM-CSF, exposure to N2O was found to dramatically enhance CFU-C recovery. Since these liquid cultures contain a strong differentiation inducer, and are unable to support CFU-C generation, the enhancement of CFU-C recovery in N2O-exposed cultures appears to be related to its ability to induce a reversible block in CFU-C differentiation. The reversible block in CFU-C maturation seen in vitro parallels clinical observations where a rapid hematologic recovery is seen in N2O-exposed patients treated with hydroxycobalamin. These observations would suggest that N2O is not markedly cytotoxic to CFU-C and that its action is, at least in part, cytostatic in nature.
Warren
D J
DJ
Department of Clinical Pharmacology, Norwegian Radium Hospital, Montebello, Oslo.
Slørdal
L
L
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009609:Nitrous Oxide / Q000494:pharmacology*
D016207:Cytokines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D009609:Nitrous Oxide