Genetic variability affects absolute and relative potencies and kinetics of the anesthetics isoflurane and sevoflurane in Drosophila melanogaster

Zachariah P G Olufs,Misha Perouansky,Barry Ganetzky,Carin A Loewen,David A Wassarman

doi:10.1038/s41598-018-20720-7

Zachariah P G Olufs, Misha Perouansky + Show 3 more

Open Access

https://doi.org/10.1038/s41598-018-20720-7

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Journal: Scientific Reports	Publication Date: Feb 5, 2018
Citations: 36	License type: open-access

Affiliation: University of Wisconsin–Madison

Abstract

Genetic variability affects the response to numerous xenobiotics but its role in the clinically-observed irregular responses to general anesthetics remains uncertain. To investigate the pharmacogenetics of volatile general anesthetics (VGAs), we developed a Serial Anesthesia Array apparatus to expose multiple Drosophila melanogaster samples to VGAs and behavioral assays to determine pharmacokinetic and pharmacodynamic properties of VGAs. We studied the VGAs isoflurane and sevoflurane in four wild type strains from the Drosophila Genetic Reference Panel, two commonly used laboratory strains (Canton S and w1118), and a mutant in Complex I of the mitochondrial electron transport chain (ND2360114). In all seven strains, isoflurane was more potent than sevoflurane, as predicted by their relative lipid solubilities, and emergence from isoflurane was slower than from sevoflurane, reproducing cardinal pharmacokinetic and pharmacodynamic properties in mammals. In addition, ND2360114 flies were more sensitive to both agents, as observed in worms, mice, and humans carrying Complex I mutations. Moreover, we found substantial variability among the fly strains both in absolute and in relative pharmacokinetic and pharmacodynamic profiles of isoflurane and sevoflurane. These data indicate that naturally occurring genetic variations measurably influence cardinal pharmacologic properties of VGAs and that flies can be used to identify relevant genetic variations.

Highlights

Isoflurane (ISO) and sevoflurane (SEVO) are chemically closely related volatile general anesthetics (VGAs) with distinct properties[1,2]
This included testing whether a hypomorphic mutation in Complex I of the mitochondrial electron transport chain (ETC) reproduces the hypersensitive phenotype observed in Caenorhabditis elegans, Mus musculus, and Homo sapiens[22,23,24,25] as well as examining the variability of PK and PD properties in a natural fly population, the Drosophila Genetic Reference Panel (DGRP)
Neither the concentration nor the duration of VGA administration is constrained by a behavioral endpoint that limits the dose of VGA that can be delivered in traditional inebriometer or separator devices[26,27,28]

Summary

Introduction

Isoflurane (ISO) and sevoflurane (SEVO) are chemically closely related volatile general anesthetics (VGAs) with distinct properties[1,2]. Establish the extent to which key pharmacokinetic (PK: ‘how an organism affects a drug’) and pharmacodynamic (PD: ‘how a drug affects an organism’) properties of ISO and SEVO are conserved in flies. This included testing whether a hypomorphic mutation in Complex I of the mitochondrial electron transport chain (ETC) reproduces the hypersensitive phenotype observed in Caenorhabditis elegans, Mus musculus, and Homo sapiens[22,23,24,25] as well as examining the variability of PK and PD properties in a natural fly population, the Drosophila Genetic Reference Panel (DGRP). Our data reveal substantial variability of PK and PD profiles for ISO and SEVO among genetically diverse wild type flies and support the usefulness of flies for pharmacogenomic and toxicological research

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Conclusion