Antiproliferative actions of inhalational anesthetics: comparisons to the valproate teratogen.
The antiproliferative potential of the volatile anesthetics isoflurane, enflurane and sevoflurane was determined and compared to the valproate teratogen. The in vitro system employed, a G1 phase proliferative arrest endpoint in C6 glioma, has served previously to discriminate agents with known teratogenic potential in vivo. Based on estimated IC(50) values that were within twice the estimated minimum aveolar concentration value, the rank antiproliferative potency of the inhalational anesthetics employed was isoflurane=enflurane>>sevoflurane. Flow cytometric analysis of growth-arrested cell populations failed to reveal specific accumulation in any cell cycle phase and the lack of a G1 phase-specific effect was confirmed by the absence of a transient, time-dependent sialylation event in synchronized cells. The antiproliferative mechanism of volatile anesthetics, and valproate, was mediated at hydrophobic binding sites, as increasing the hydration sphere of the drug-micelle complex, using the hygroscopic qualities of the dimethylsulfoxide vehicle, completely reversed this effect. Our findings suggest inhalational anesthetics lack the specific in vitro characteristics of the valproate teratogen.
O'Leary
G
G
University Department of Anesthesia, Mater Misericordiae Hospital, Dublin, Ireland.
Bacon
C L
CL
Odumeru
O
O
Fagan
C
C
Fitzpatrick
T
T
Gallagher
H C
HC
Moriarty
D C
DC
Regan
C M
CM
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004737:Enflurane / Q000494:pharmacology; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D005910:Glioma; D007530:Isoflurane / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008738:Methyl Ethers / Q000494:pharmacology; D008823:Micelles; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D009363:Neoplasm Proteins / Q000032:analysis / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D010835:Phytohemagglutinins; D000077149:Sevoflurane; D012997:Solvents / Q000494:pharmacology; D013723:Teratogens / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D014635:Valproic Acid / Q000494:pharmacology*
D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D008823:Micelles; D009363:Neoplasm Proteins; D010835:Phytohemagglutinins; D012997:Solvents; D013723:Teratogens; C100156:leukoagglutinins, plants; D000077149:Sevoflurane; D014635:Valproic Acid; D004737:Enflurane; D007530:Isoflurane; D007770:L-Lactate Dehydrogenase; D019158:N-Acetylneuraminic Acid; D004121:Dimethyl Sulfoxide