Risk Assessment of Psychotropic Drugs on Mitochondrial Function Using In Vitro Assays

Area of Science:

• Biochemistry
• Toxicology
• Pharmacology

Background:

• Mitochondria play a crucial role in cellular energy production and are implicated in drug-induced organ toxicities.
• The precise molecular mechanisms underlying drug-induced mitochondrial toxicity remain largely uncharacterized.

Purpose of the Study:

• To investigate the effects of 22 psychotropic drugs on mitochondrial function using in vitro assays.
• To elucidate the mechanisms of drug-induced mitochondrial toxicity and inform clinical safety profiles.

Main Methods:

• Utilized acute extracellular flux assays in HepG2 cells to identify drug effects on mitochondrial respiration.
• Employed permeabilized HepG2 cells to determine minimum effective concentrations for complex-I-linked respiration inhibition.
• Assessed complex-II-linked respiration in isolated rat liver mitochondria to identify electron transport chain (ETC) inhibitors and uncouplers.

Main Results:

• Identified aripiprazole, phenytoin, and fluoxetine as ETC inhibitors; reserpine as an uncoupler; quetiapine, carbamazepine, buspirone, and tianeptine as substrate inhibitors; and chlorpromazine and valproic acid as cytotoxic compounds in HepG2 cells.
• Determined minimum effective concentrations for complex-I inhibition by quetiapine (66.3 µM), valproic acid (6730 µM), buspirone (44.5 µM), and fluoxetine (72.1 µM).
• Characterized haloperidol as an ETC inhibitor, chlorpromazine as an uncoupler and ETC inhibitor (IC50 = 135 µM), and olanzapine as a mild membrane potential dissipator (50 µM) in rat liver mitochondria.

Conclusions:

• Elucidated specific mechanisms of mitochondrial toxicity for several psychotropic drugs.
• Provided valuable insights into the mitochondrial safety profiles of psychotropic medications, aiding clinical decision-making.