Cytotoxicity of S-conjugates of the sevoflurane degradation product fluoromethyl-2,2-difluoro-1-(trifluoromethyl) vinyl ether (Compound A) in a human proximal tubular cell line

Altuntas, T. Gul; Zager, Richard A.; Kharasch, Evan D.

doi:10.1016/s0041-008x(03)00336-3

Cited by 20 publications

(17 citation statements)

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“…Sevoflurane has gained interest due to a number of advantages over other anesthetics, however its use also has certain limitations, including neuronal cytotoxicity. This cytotoxicity has been documented in several studies (7,33). membrane disruption and necrosis.…”

Section: Discussionmentioning

confidence: 71%

Sevoflurane‑induced neurotoxicity is driven by OXR1 post‑transcriptional downregulation involving hsa‑miR‑302e

et al. 2018

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Sevoflurane is a common anesthetic agent used in surgical settings and previous studies have indicated that it exerts a neurotoxic effect. However, the molecular mechanism underlying this side effect is unknown. In addition, the human microRNA‑302 (hsa‑miR‑302) family members have been reported to be involved in neuronal cell development and biology. Thus, the present study aimed to investigate the potential implication of hsa‑miR‑302e in the sevoflurane‑induced cytotoxicity on human hippocampal cells (HN‑h). HN‑h cells were transfected with hsa‑miR‑302e mimic, hsa‑miR‑302e inhibitor or negative controls and subsequently exposed to different concentrations of sevoflurane. An MTT assay was used to assess the cytotoxicity of sevoflurane on HN‑h cells. Cell apoptosis was determined by flow cytometry. The levels of lactate dehydrogenase release, reactive oxygen species, lipid peroxidation and intracellular calcium (Ca2+) were additionally detected. Reverse transcription‑quantitative polymerase chain reaction and western blotting were conducted to determine mRNA and protein expression, respectively. A luciferase assay was performed for validating the targeting of OXR1 by hsa‑miR‑302e. The results indicated that sevoflurane induced a decrease in cell viability, malondialdehyde and reactive oxygen species production, lactate dehydrogenase release, intracellular Ca2+ production, calcium/calmodulin‑dependent protein kinase II phosphorylation and apoptosis. In addition, treatment with sevoflurane induced the expression of hsa‑miR‑302e while the expression of its target, oxidation resistance gene 1 (OXR1), was significantly downregulated. Inhibition of hsa‑miR‑302e expression protected neuronal cells from sevoflurane cytotoxicity. Mechanistic studies demonstrated that OXR1 was a direct target of hsa‑miR‑302e. Furthermore, the overexpression of OXR1 abolished the effect of sevoflurane on neuronal cells. The results of the present study indicated that sevoflurane exerts its neurotoxic effect by regulating the hsa‑miR‑302e/OXR1 axis. Therefore, the manipulation of the hsa‑miR‑302e/OXR1 pathway will be useful for preventing sevoflurane‑induced neurotoxicity.

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Section: Discussionmentioning

confidence: 71%

Sevoflurane‑induced neurotoxicity is driven by OXR1 post‑transcriptional downregulation involving hsa‑miR‑302e

et al. 2018

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“…Conjugation may not necessarily inactivate, there are many examples of Phase II (conjugate) bioactivation in mammals [294][295][296][297][298][299][300][301][302][303][304][305]. An example of a deleterious glucuronidation is glucuronidation of a carboxy group, yielding a reactive acyl glucuronide.…”

Section: Metabolic Inactivation Of Endogenous Steroidsmentioning

confidence: 99%

The Use of Metabolising Systems for In Vitro Testing of Endocrine Disruptors

Jacobs¹,

Janssens²,

Bernauer

et al. 2008

CDM

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Legislation and prospective legislative proposals in for instance the USA, Europe, and Japan require, or may require that chemicals are tested for their ability to disrupt the hormonal systems of mammals. Chemicals found to test positive are considered to be endocrine active substances (EAS) and may be putative endocrine disruptors (EDs). To date, there is still little or no experience with incorporating metabolic and toxicokinetic aspects into in vitro tests for EAS. This is a situation in sharp contrast to genotoxicity testing, where in vitro tests are routinely conducted with and without metabolic capacity. Originally prepared for the Organisation of Economic Cooperation and Development (OECD), this detailed review paper reviews why in vitro assays for EAS should incorporate mammalian systems of metabolism and metabolic enzyme systems, and indicates how this could be done. The background to ED testing, the available test methods, and the role of mammalian metabolism in the activation and the inactivation of both endogenous and exogenous steroids are described. The available types of systems are compared, and the potential problems in incorporating systems in in vitro tests for EAS, and how these might be overcome, are discussed. Lastly, some recommendations for future activities are made.

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“…Their main negative influence on the environment is that they accumulate as pollutants. Nevertheless, it should be mentioned that their monomeric components can exert a toxic effect, as shown by the cytotoxic effect that tetrafluorine ethylene and fluorinated vinyl ethers have been found to have on warmblooded animals (Knofler and Neupert, 1985;Keller et al, 2000;Altuntas et al, 2003).…”

Section: Growth Of Microorganisms On Polymeric Materialsmentioning

confidence: 99%

Physical and chemical aspects of long‐term biodeterioration of some polymers and composites

Lugauskas

Prosychevas

Levinskaitė

et al. 2004

Environmental Toxicology

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A biodeterioration study was performed on synthetic polymeric materials including homogenous film made from poly(tetrafluorine ethylene), copolymer film made from tetrafluorine ethylene and perfluoromethyl vinyl ether, vulcanized rubber containing natural caoutchouc, and vulcanized rubber, the main component of which was synthetic butadiene nitrile caoutchouc. The materials were exposed for 12 years to the open air, in mycological containers, and in a cellar in maritime climate conditions: air humidity 72%-90% and seasonal average temperature of 17 degrees C in summer and -2.5 degrees C in winter. The studies of optical and electron microscopy revealed that microorganisms were able to develop not only on the surface of the materials but also to penetrate inside into deeper layers. The fungi that produced the most intensive deterioration in the fluorine polymers and vulcanized rubbers belonged to the Alternaria, Aspergillus, Aureobasidium, Cladosporium, Penicillium, Oidiodendron and Trichoderma genera. The fungi Aspergillus fumigatus, A. niger, Aureobasidium pullulans, and Trichoderma viride produced the most intensive deterioration in the fluorine films, whereas Alternaria tenuissima, Cladosporium herbarum, C. sphaerospermum, and fungi of the Oidiodendron genus were widespread on vulcanized rubbers. Fungi of the Aspergillus and Penicillium genera prevailed on both fluorine films and rubbers exposed in a cellar. Infrared spectroscopy indicated that the structures of poly(tetrafluorine ethylene) and the copolymer of tetrafluorine ethylene and perfluoromethyl vinyl ether did not change after the 12-year exposure; only insignificant changes in surface morphology were observed by optical microscopy. Vulcanized rubber made both from natural and from synthetic caoutchouc exposed for the same length of time showed rather evident changes in appearance and structure. X-ray graphical analysis revealed that new crystallization of the caoutchouc and a possible change in chemical composition of the fillers had occurred.

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Cytotoxicity of S-conjugates of the sevoflurane degradation product fluoromethyl-2,2-difluoro-1-(trifluoromethyl) vinyl ether (Compound A) in a human proximal tubular cell line

Cited by 20 publications

References 50 publications

Sevoflurane‑induced neurotoxicity is driven by OXR1 post‑transcriptional downregulation involving hsa‑miR‑302e

Sevoflurane‑induced neurotoxicity is driven by OXR1 post‑transcriptional downregulation involving hsa‑miR‑302e

The Use of Metabolising Systems for In Vitro Testing of Endocrine Disruptors

Physical and chemical aspects of long‐term biodeterioration of some polymers and composites

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