The minimum dose needed to induce anesthesia, known as minimum alveolar concentration (MAC), of an inhaled anesthetic varies among patients, with a typical coefficient of variation around 10% in humans. This individual variability in MAC arises from genetic differences, environmental or physiological factors (such as age or brain temperature), and measurement error. Studies in genetically tractable invertebrates like Caenorhabditis elegans and Drosophila melanogaster have identified genes that influence anesthetic sensitivity, offering insight into the molecular basis of these differences(1,2). Because vertebrates respond differently to anesthetics, complementary studies in mammals, particularly mice, have been essential to furthering the field.
In a 1999 study, an experimental investigation was performed in which C. elegans nematodes were exposed to volatile anesthetics such as isoflurane and enflurane(1). Sequencing across specimens with differing levels of sensitivity pointed to a single missense mutation converting arginine to lysine at position 290 in the GAS-1 protein. GAS-1 was shown to be homologous to the 49-kDa subunit of mitochondrial NADH dehydrogenase, a key component of complex I in the respiratory chain. The mutation caused hypersensitivity to both isoflurane and enflurane. These findings suggest that mitochondrial complex I function plays a critical role in determining anesthetic sensitivity. Identifying GAS-1 as a molecular target provided a framework for linking genetic variation to physiological mechanisms underlying responses to anesthesia in eukaryotes(1).
In a 2000 study, researchers examined at 81 male mice who were exposed to halothane, desflurane, or isoflurane(3). Significant variability in MAC values were observed among different strains, with ranges of 39% for desflurane, 44% for isoflurane, and 55% for halothane, indicating substantial inter-strain variability. Measurement error was minimal, with reliability coefficients near 0.99 for all anesthetics, confirming that observed differences reflected true biological variation. Regression analyses showed that common determinants accounted for 20%–60% of the variance, while anesthetic-specific factors explained the remainder (3). This suggests that multiple genes, rather than a single gene, underlie variability in anesthetic sensitivity among different genotypes. The results provide a foundation for mapping quantitative trait loci and understanding genetic contributions to anesthetic responses.
Additionally, a retrospective observational cohort study was conducted on 30,125 adult patients who had surgery with inhalational anesthetics (sevoflurane or isoflurane, with or without nitrous oxide)(4). The study found substantial individual variability in age-adjusted MAC ratios and demonstrated that factors such as sex, race, prior drug use, hemodynamics, and anesthetic management influenced anesthetic dosing. Further analyses also revealed dynamic titration of anesthetics in response to changes in mean arterial pressure, highlighting within-patient variability as well. In particular, female patients received lower mean MAC ratios4, despite clinical evidence that they typically have higher anesthetic requirements(5).
Both preclinical and clinical studies consistently demonstrate substantial variability in anesthetic sensitivity across individuals and genotypes. Genetic factors, physiological characteristics, and intraoperative management all contribute to this variability, with multiple genes, rather than a single determinant, likely influencing response(3). These insights underscore the importance of personalized anesthetic dosing strategies that integrate genetic, physiological, and real-time clinical data to optimize patient care.
References
1. Kayser EB, Morgan Phil G, Sedensky Margaret M. GAS-1 . Anesthesiology. 1999;90(2):545-554. https://doi.org/10.1097/00000542-199902000-00031
2. Campbell DJ, Nash HA. Use of Drosophila mutants to distinguish among volatile general anesthetics. Proceedings of the National Academy of Sciences of the United States of America. 1994;91(6):2135-2139. https://doi.org/10.1073/pnas.91.6.2135
3. Sonner JM, Gong D, Eger EI. Naturally Occurring Variability in Anesthetic Potency Among Inbred Mouse Strains. Anesthesia & Analgesia. 2000;91(3):720-726. https://doi.org/10.1213/00000539-200009000-00042
4. Douville NJ, Jewell ES, Zhao X, et al. Clinical and Genetic Factors Associated with Intraoperative Minimum Alveolar Concentration Ratio: A Single-center Retrospective Cohort and Genome-wide Association Study. Anesthesiology. 2025;143(3):541-558. https://doi.org/10.1097/aln.0000000000005602
5. Wasilczuk AZ, Rinehart C, Aggarwal A, et al. Hormonal basis of sex differences in anesthetic sensitivity. Proceedings of the National Academy of Sciences of the United States of America. 2024;121(3). https://doi.org/10.1073/pnas.2312913120
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