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. 1994 Oct 11;91(21):10054–10058. doi: 10.1073/pnas.91.21.10054

Genetic differences affecting the potency of stereoisomers of halothane.

M M Sedensky 1, H F Cascorbi 1, J Meinwald 1, P Radford 1, P G Morgan 1
PMCID: PMC44956  PMID: 7937836

Abstract

The mechanism of action of volatile anesthetics is the subject of some debate. Much of the controversy has centered on whether the site of such actions is purely lipid in nature or may contain a protein target. This report studies the interaction of stereoisomers of halothane on the wild type and on a variety of genetic mutants of Caenorhabditis elegans. The mutants studied have previously been shown to have altered sensitivities to volatile anesthetics. In one mutant, fc34, (R)-halothane [the (+) isomer] was 3 times more potent than its S (-) isomer. Other mutants and wild-type animals displayed more modest differences in sensitivity to the enantiomers. The results indicate that a genetic pathway exists in C. elegans controlling sensitivity to halothane and that both lipid and protein targets may mediate halothane's effects.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Brenner S. The genetics of Caenorhabditis elegans. Genetics. 1974 May;77(1):71–94. doi: 10.1093/genetics/77.1.71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Firestone L. L., Sauter J. F., Braswell L. M., Miller K. W. Actions of general anesthetics on acetylcholine receptor-rich membranes from Torpedo californica. Anesthesiology. 1986 Jun;64(6):694–702. doi: 10.1097/00000542-198606000-00004. [DOI] [PubMed] [Google Scholar]
  3. Franks N. P., Lieb W. R. Do general anaesthetics act by competitive binding to specific receptors? Nature. 1984 Aug 16;310(5978):599–601. doi: 10.1038/310599a0. [DOI] [PubMed] [Google Scholar]
  4. Franks N. P., Lieb W. R. Molecular and cellular mechanisms of general anaesthesia. Nature. 1994 Feb 17;367(6464):607–614. doi: 10.1038/367607a0. [DOI] [PubMed] [Google Scholar]
  5. Franks N. P., Lieb W. R. Molecular mechanisms of general anaesthesia. Nature. 1982 Dec 9;300(5892):487–493. doi: 10.1038/300487a0. [DOI] [PubMed] [Google Scholar]
  6. Franks N. P., Lieb W. R. Selective actions of volatile general anaesthetics at molecular and cellular levels. Br J Anaesth. 1993 Jul;71(1):65–76. doi: 10.1093/bja/71.1.65. [DOI] [PubMed] [Google Scholar]
  7. Franks N. P., Lieb W. R. Stereospecific effects of inhalational general anesthetic optical isomers on nerve ion channels. Science. 1991 Oct 18;254(5030):427–430. doi: 10.1126/science.1925602. [DOI] [PubMed] [Google Scholar]
  8. Harris B., Moody E., Skolnick P. Isoflurane anesthesia is stereoselective. Eur J Pharmacol. 1992 Jul 7;217(2-3):215–216. doi: 10.1016/0014-2999(92)90875-5. [DOI] [PubMed] [Google Scholar]
  9. Janoff A. S., Pringle M. J., Miller K. W. Correlation of general anesthetic potency with solubility in membranes. Biochim Biophys Acta. 1981 Nov 20;649(1):125–128. doi: 10.1016/0005-2736(81)90017-1. [DOI] [PubMed] [Google Scholar]
  10. Jones M. V., Harrison N. L. Effects of volatile anesthetics on the kinetics of inhibitory postsynaptic currents in cultured rat hippocampal neurons. J Neurophysiol. 1993 Oct;70(4):1339–1349. doi: 10.1152/jn.1993.70.4.1339. [DOI] [PubMed] [Google Scholar]
  11. Kendig J. J., Trudell J. R., Cohen E. N. Halothane stereoisomers: lack of stereospecificity in two model systems. Anesthesiology. 1973 Nov;39(5):518–524. [PubMed] [Google Scholar]
  12. Krishnan K. S., Nash H. A. A genetic study of the anesthetic response: mutants of Drosophila melanogaster altered in sensitivity to halothane. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8632–8636. doi: 10.1073/pnas.87.21.8632. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. MacIver M. B., Tauck D. L., Kendig J. J. General anaesthetic modification of synaptic facilitation and long-term potentiation in hippocampus. Br J Anaesth. 1989 Mar;62(3):301–310. doi: 10.1093/bja/62.3.301. [DOI] [PubMed] [Google Scholar]
  14. McIntire S. L., Jorgensen E., Kaplan J., Horvitz H. R. The GABAergic nervous system of Caenorhabditis elegans. Nature. 1993 Jul 22;364(6435):337–341. doi: 10.1038/364337a0. [DOI] [PubMed] [Google Scholar]
  15. Meinwald J., Thompson W. R., Pearson D. L., König W. A., Runge T., Francke W. Inhalational anesthetics stereochemistry: optical resolution of halothane, enflurane, and isoflurane. Science. 1991 Feb 1;251(4993):560–561. doi: 10.1126/science.1846702. [DOI] [PubMed] [Google Scholar]
  16. Morgan P. G., Sedensky M. M., Meneely P. M., Cascorbi H. F. The effect of two genes on anesthetic response in the nematode Caenorhabditis elegans. Anesthesiology. 1988 Aug;69(2):246–251. doi: 10.1097/00000542-198808000-00015. [DOI] [PubMed] [Google Scholar]
  17. Morgan P. G., Sedensky M., Meneely P. M. Multiple sites of action of volatile anesthetics in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 1990 Apr;87(8):2965–2969. doi: 10.1073/pnas.87.8.2965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Sedensky M. M., Meneely P. M. Genetic analysis of halothane sensitivity in Caenorhabditis elegans. Science. 1987 May 22;236(4804):952–954. doi: 10.1126/science.3576211. [DOI] [PubMed] [Google Scholar]
  19. Ueda I., Kamaya H. Molecular mechanisms of anesthesia. Anesth Analg. 1984 Oct;63(10):929–945. [PubMed] [Google Scholar]
  20. Waud D. R. On biological assays involving quantal responses. J Pharmacol Exp Ther. 1972 Dec;183(3):577–607. [PubMed] [Google Scholar]

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