Effects of Halothane on Human and Rat Hepatocyte Cultures

Mallédant, Yannick; Siproudhis, L.; Tanguy, M.; Clerc, C.; Chesné, Christophe; Saint-Marc, Colette; Guillouzo, André

doi:10.1097/00000542-199003000-00022

Cited by 22 publications

(11 citation statements)

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“…Cytotoxicity in isolated hepatocytes from halothane has been demonstrated (172,268,269). Rat cells are more sensitive than their human counterparts (172). In a recent study using enriched periportal and centrilobular hepatocyte subpopulations in primary culture, we found that the latter were the most sensitive to the anesthetic and that increased reductive metabolism of halothane induced by decreasing oxygen concentration is not a critical parameter for the occurrence of liver damage in these cells (270).…”

Section: However Survival and Metabolic Compe-mentioning

confidence: 82%

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Liver cell models in in vitro toxicology.

Guillouzo

1998

Environ Health Perspect

300

125

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In vitro liver preparations are increasingly used for the study of hepatotoxicity of chemicals. In recent years their actual advantages and limitations have been better defined. The cell models, slices, and mainly primary hepatocyte cultures, appear to be the most powerful in vitro systems, as liver-specific functions and responsiveness to inducers are retained either for a few days or several weeks depending on culture conditions. Maintenance of phase and phase 11 xenobiotic metabolizing enzyme activities allows various chemical investigations to be performed, including determination of kinetic parameters, metabolic profile, interspecies comparison, inhibition and induction effects, and drug-drug interactions. In vitro liver cell models also have various applications in toxicology: screening of cytotoxic and genotoxic compounds, evaluation of chemoprotective agents, and determination of characteristic liver lesions and associated biochemical mechanisms induced by toxic compounds. Extrapolation of the results to the in vivo situation remains a matter of debate. Presently, the most convincing applications of liver cell models are the studies on different aspects of metabolism and mechanisms of toxicity. For the future, there is a need for better culture conditions and differentiated hepatocyte cell lines to overcome the limited availability of human liver tissues. In addition, strategies for in vitro analysis of potentially toxic chemicals must be better defined. Environ Health Perspect 106(Suppl 2):511-532 (1998). http.//ehpnetl.niehs.nih.gov/docs/1998/Suppl-2/51 1-532guillouzo/abstract.html

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Section: However Survival and Metabolic Compe-mentioning

confidence: 82%

“…Cytotoxicity in isolated hepatocytes from halothane has been demonstrated (172,268,269). Rat cells are more sensitive than their human counterparts (172).…”

Section: However Survival and Metabolic Compe-mentioning

confidence: 99%

Liver cell models in in vitro toxicology.

Guillouzo

1998

Environ Health Perspect

300

125

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“…This has been reported in a number of different systems, including intact animals (23-25), perfused organs (10, 40, 41), tissue slices in culture (15-18), and cells in culture (3,6,8,21,35). Studies regarding effects of volatile anesthetics on protein synthesis in perfused rat liver, the system employed in the work reported here, demonstrate that halothane exposure produces a rapid and dose-dependent inhibition of translation initiation affecting synthesis of both secreted and retained proteins (10,12).…”

mentioning

confidence: 81%

Inhibition of mammalian translation initiation by volatile anesthetics

Palmer¹,

Rannels²,

Kimball³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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Volatile anesthetics are essential for modern medical practice, but sites and mechanisms of action for any of their numerous cellular effects remain largely unknown. Previous studies with yeast showed that volatile anesthetics induce nutrient-dependent inhibition of growth through mechanisms involving inhibition of mRNA translation. Studies herein show that the volatile anesthetic halothane inhibits protein synthesis in perfused rat liver at doses ranging from 2 to 6%. A marked disaggregation of polysomes occurs, indicating that inhibition of translation initiation plays a key role. Dose-and time-dependent alterations that decrease the function of a variety of translation initiation processes are observed. At 6% halothane, a rapid and persistent increase in phosphorylation of the ␣-subunit of eukaryotic translation initiation factor (eIF)2 occurs. This is accompanied by inhibition of activity of the guanine nucleotide exchange factor eIF2B that is responsible for GDP-GTP exchange on eIF2. At lower doses, neither eIF2␣ phosphorylation nor eIF2B activity is altered. After extended exposure to 6% halothane, alterations in two separate responses regulated by the target of rapamycin pathway occur: 1) redistribution of eIF4E from its translation-stimulatory association with eIF4G to its translation-inactive complex with eIF4E-binding protein-1; and 2) decreased phosphorylation of ribosomal protein S6 (rpS6) with a corresponding decrease in active forms of a kinase that phosphorylates rpS6 (p70 S6K1 ). Changes in the association of eIF4E and eIF4G are observed only after extended exposure to low anesthetic doses. Thus dose-and time-dependent alterations in multiple processes permit liver cells to adapt translation to variable degrees and duration of stress imposed by anesthetic exposure. halothane; eukaryotic translation initiation factor 2␣ phosphorylation; mammalian target of rapamycin pathway ALTHOUGH VOLATILE ANESTHETICS revolutionized medical practice when introduced in 1846, the mechanisms of action responsible for the physiological effects of these drugs remain essentially unknown. In addition to affecting cells of the central nervous system, these drugs affect all cells, tissues, and organisms examined (4,26,36). Molecular genetic studies with the small, relatively simple eukaryote Saccharomyces cerevisiae (yeast) provide an opportunity for gaining insight regarding physiologically relevant effects of these drugs (28) and generating hypotheses that are testable in more complex eukaryotes. Extensive similarities exist between the activity of these drugs in mammals and simpler eukaryotes, such as yeast, suggesting conservation of cellular mechanisms responsible for the responses (28,34,45). These similarities include rapid and reversible induction of responses, a sharp dose-response curve, correlation between the lipophilicity of various anesthetics and their potency for inducing responses (termed the Meyer-Overton relationship), additivity of doses of different anesthetics in producing effects, and lack of effec...

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“…Isoflurane exposure has been shown to cause cell damage in various neuronal and non-neuronal tissues and cells, including hippocampal slices (Wise-Faberowski et al, 2005), lymphocytes Yang et al, 2008), neuroglioma cells (Xie et al, 2007;Zhang et al, 2008), hepatocytes (Malledant et al, 1990), gingival fibroblasts (Chang and Chou, 2001), the PC12 neurosecretory cell line Liang et al, 2008), and striatal neurons . Interestingly, these cells have different intrinsic vulnerability to anesthetic toxicity, with lymphocytes generally being more vulnerable than neurons (Wei et al, 2005Liang et al, 2008).…”

mentioning

confidence: 99%

Anesthetic-Induced Neurodegeneration Mediated via Inositol 1,4,5-Trisphosphate Receptors

Zhao

Chen

et al. 2010

J Pharmacol Exp Ther

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The commonly used general anesthetic isoflurane induces widespread neurodegeneration in the developing mammalian brain through poorly understood mechanisms. We have investigated whether excessive Ca 2ϩ release from the endoplasmic reticulum via overactivation of inositol 1,4,5-trisphosphate receptors (InsP 3 Rs) is a contributing factor in such neurodegeneration in rodent primary cultured neurons and developing rat brain. We also investigated the correlation between isoflurane exposure and cognitive decline in rats at 1 month of age. Our results show that isoflurane increases cytosolic calcium in the primary cortical neurons through release from the endoplasmic reticulum and influx from the extracellular space. Pharmacological inhibition of InsP 3 R activity and knockdown of its expression nearly abolishes the isoflurane-mediated elevation of the cytosolic calcium concentration and cell death in rodent primary cortical and hippocampal neurons. Inhibition of InsP 3 R activity by its antagonist xestospongin C significantly inhibits neurodegeneration induced by isoflurane at clinically used concentration in the developing brain of postnatal day 7 rats. Moreover, our results show that isoflurane activates ␤-site amyloid ␤ precursor protein-cleaving enzyme via activation of the InsP 3 R. We also noted that mice exposed to isoflurane during early postnatal development showed transient memory and learning impairments, which did not correlate well with the noted neuropathological defects. Taken together, our results suggest that Ca 2ϩ dysregulation through overactivation of the InsP 3 R may be a contributing factor in the mechanism of isoflurane-induced neurodegeneration in rodent neuronal cell culture and during brain development.

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Effects of Halothane on Human and Rat Hepatocyte Cultures

Cited by 22 publications

References 0 publications

Liver cell models in in vitro toxicology.

Liver cell models in in vitro toxicology.

Inhibition of mammalian translation initiation by volatile anesthetics

Anesthetic-Induced Neurodegeneration Mediated via Inositol 1,4,5-Trisphosphate Receptors

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