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Cytoskeleton interruption in human hepatoma HepG2 cells induced by ketamine occurs possibly through suppression of

Huai-Chia Chang1, Ta-Liang Chen, Ruei-Ming Chen

  • 1Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wu-Xing St., Taipei 110, Taiwan.

Drug Metabolism and Disposition: the Biological Fate of Chemicals
|October 11, 2008
PubMed

Insights

Therapeutic ketamine disrupts cell structure by affecting F-actin and microtubule cytoskeletons in liver cells. This impacts drug metabolism by reducing CYP3A4 activity.

Area of Science:

  • Hepatology
  • Cell Biology
  • Pharmacology

Background:

  • Cytoskeletons are crucial for regulating drug metabolism in hepatocytes.
  • Ketamine is an anesthetic with potential effects on cellular functions.

Purpose of the Study:

  • To investigate ketamine's impact on F-actin and microtubular cytoskeletons in human hepatoma HepG2 cells.
  • To elucidate the molecular mechanisms underlying ketamine's effects on cellular structure and function.

Main Methods:

  • Exposure of HepG2 cells to clinically relevant ketamine concentrations.
  • Assessment of cell viability, cytoskeletal integrity, intracellular calcium levels, ATP levels, mitochondrial membrane potential, and Complex I activity.
  • Confocal microscopy for calcium mobilization analysis.
  • Measurement of CYP3A4 expression and activity.

Main Results:

  • Ketamine at therapeutic concentrations disrupted F-actin and microtubular cytoskeletons without affecting cell viability.
  • Ketamine decreased intracellular calcium levels, suppressed calcium influx, reduced cellular ATP, and lowered mitochondrial membrane potential and Complex I activity.
  • Ketamine-induced cytoskeletal disruption led to suppressed CYP3A4 expression and reduced its metabolic activity.

Conclusions:

  • Therapeutic ketamine disrupts F-actin and microtubular cytoskeletons in HepG2 cells.
  • Mechanisms involve suppressed intracellular calcium mobilization and ATP synthesis, linked to mitochondrial dysfunction.
  • Cytoskeletal disruption by ketamine reduces CYP3A4 activity, impacting drug metabolism.

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