Stereoselectivity of Isoflurane in Adhesion Molecule Leukocyte Function-Associated Antigen-1

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Stereoselectivity of Isoflurane in Adhesion Molecule Leukocyte Function-Associated Antigen-1

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Title: Stereoselectivity of Isoflurane in Adhesion Molecule Leukocyte Function-Associated Antigen-1
Author: Bu, Weiming; Pereira, Luis M.; Eckenhoff, Roderic G.; Yuki, Koichi

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Citation: Bu, Weiming, Luis M. Pereira, Roderic G. Eckenhoff, and Koichi Yuki. 2014. “Stereoselectivity of Isoflurane in Adhesion Molecule Leukocyte Function-Associated Antigen-1.” PLoS ONE 9 (5): e96649. doi:10.1371/journal.pone.0096649. http://dx.doi.org/10.1371/journal.pone.0096649.
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Abstract: Background: Isoflurane in clinical use is a racemate of S- and R-isoflurane. Previous studies have demonstrated that the effects of S-isoflurane on relevant anesthetic targets might be modestly stronger (less than 2-fold) than R-isoflurane. The X-ray crystallographic structure of the immunological target, leukocyte function-associated antigen-1 (LFA-1) with racemic isoflurane suggested that only S-isoflurane bound specifically to this protein. If so, the use of specific isoflurane enantiomers may have advantage in the surgical settings where a wide range of inflammatory responses is expected to occur. Here, we have further tested the hypothesis that isoflurane enantioselectivity is apparent in solution binding and functional studies. Methods: First, binding of isoflurane enantiomers to LFA-1 was studied using 1-aminoanthracene (1-AMA) displacement assays. The binding site of each enantiomer on LFA-1 was studied using the docking program GLIDE. Functional studies employed the flow-cytometry based ICAM binding assay. Results: Both enantiomers decreased 1-AMA fluorescence signal (at 520 nm), indicating that both competed with 1-AMA and bound to the αL I domain. The docking simulation demonstrated that both enantiomers bound to the LFA-1 “lovastatin site.” ICAM binding assays showed that S-isoflurane inhibited more potently than R-isoflurane, consistent with the result of 1-AMA competition assay. Conclusions: In contrast with the x-ray crystallography, both enantiomers bound to and inhibited LFA-1. S-isoflurane showed slight preference over R-isoflurane.
Published Version: doi:10.1371/journal.pone.0096649
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4011845/pdf/
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Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:12407047
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