Journal: The journal of pharmacology and experimental therapeutics

Abbreviation

J Pharmacol Exp Ther

Publisher

American Society for Pharmacology and Experimental Therapeutics

Journal Volumes

ISSN

0022-3565
1521-0103

Description

Filters

2009 - 200912010 - 20201
Reset filters

Search Results

Publications 1 - 2 of 2
  • Natural Variation within the Neuronal Nicotinic Acetylcholine Receptor Cluster on Human Chromosome 15q24
    Item type: Journal Article
    Rana, Brinda K.; Wessel, Jennifer; Mahboubi, Vafa; et al. (2009)
    The journal of pharmacology and experimental therapeutics
  • Untargeted Metabolomics Reveals Anaerobic Glycolysis as a Novel Target of the Hepatotoxic Antidepressant Nefazodone
    Item type: Journal Article
    Krajnc, Evelin; Visentin, Michele; Gai, Zhibo; et al. (2020)
    The journal of pharmacology and experimental therapeutics
    Mitochondrial damage is considered a hallmark of drug-induced liver injury (DILI). However, despite the common molecular etiology, the evolution of the injury is usually unpredictable, with some cases that are mild and reversible upon discontinuation of the treatment and others characterized by irreversible acute liver failure. This suggests that additional mechanisms of damage play a role in determining the progression of the initial insult. To uncover novel pathways potentially involved in DILI, we investigated in vitro the metabolic perturbations associated with nefazodone, an antidepressant associated with acute liver failure. Several pathways associated with ATP production, including gluconeogenesis, anaerobic glycolysis, and oxidative phosphorylation, were altered in human hepatocellular carcinoma–derived (Huh7) cells after 2-hour exposure to a 50 μM extracellular concentration of nefazodone. In the presence or absence of glucose, ATP production of Huh7 cells was glycolysis- and oxidative phosphorylation–dependent, respectively. In glucose-containing medium, nefazodone-induced ATP depletion from Huh7 cells was biphasic. Huh7 cells in glucose-free medium were more sensitive to nefazodone than those in glucose-containing medium, losing the biphasic inhibition. Nefazodone-induced ATP depletion in primary cultured mouse hepatocytes, mainly dependent on oxidative phosphorylation, was monophasic. At lower extracellular concentrations, nefazodone inhibited the oxygen consumption of Huh7 cells, whereas at higher extracellular concentrations, it also inhibited the extracellular acidification. ATP content was rescued by increasing the extracellular concentration of glucose. In conclusion, nefazodone has a dual inhibitory effect on mitochondrial-dependent and mitochondrial-independent ATP production. © 2020 by The American Society for Pharmacology and Experimental Therapeutics.
Publications 1 - 2 of 2