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Inhibition of mitochondrial function: An alternative explanation for the antipyretic and hypothermic actions of

Shazma Bashir1, Winston A Morgan1

  • 1The Medicines Research Group, School of Health, Sport and Bioscience, University of East London, Stratford Campus, Water Lane, London E15 4LZ, UK.

Life Sciences
|November 15, 2022
PubMed
Abstract

Insights

Acetaminophen directly inhibits mitochondrial function and fatty acid oxidation, contributing to its fever-reducing effects. This mechanism offers potential for developing new, safer antipyretics.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Cell Biology

Background:

  • Acetaminophen is a common fever reducer with limited anti-inflammatory effects.
  • Overdosing on acetaminophen can lead to mitochondrial dysfunction and damage, primarily through its metabolite N-acetyl-p-benzoquinone imine (NAPQI).
  • The precise mechanism behind acetaminophen's antipyretic and hypothermic properties, specifically its impact on mitochondrial function, remains under-investigated.

Purpose of the Study:

  • To investigate whether the inhibition of mitochondrial function, particularly fatty acid uptake and oxidation, is responsible for acetaminophen's antipyretic and hypothermic effects.
  • To compare the effects of acetaminophen and its toxic metabolite NAPQI on mitochondrial respiration.

Main Methods:

  • Mitochondrial function and fatty acid oxidation (FAO) were assessed by measuring oxygen consumption rate (OCR) using an XFp Analyzer.
  • OCR was measured in isolated mitochondria and 3T3-L1 adipocytes under basal and stimulated conditions.
  • Experiments involved treating cells and mitochondria with acetaminophen, NAPQI, etomoxir, and other mitochondrial stress compounds.

Main Results:

  • Acetaminophen (10 mM) significantly decreased FAO in adipocytes by 31% (basal) and 29% (palmitate-stimulated).
  • Acetaminophen (10 mM) reduced basal and adrenergic-stimulated OCR by 34% and inhibited mitochondrial complexes I and II at 5 mM.
  • NAPQI (50 μM) demonstrated greater potency than acetaminophen in reducing FAO, respiratory capacity, maximum respiratory rates, and ATP production.

Conclusions:

  • Acetaminophen directly inhibits mitochondrial function at concentrations relevant to fever reduction in mammals.
  • This inhibition of mitochondrial function and heat generation is a key factor in acetaminophen's antipyretic and hypothermic actions.
  • Understanding these mechanisms could pave the way for developing novel antipyretics with improved safety profiles, avoiding the toxicity associated with current medications.
Keywords:
AcetaminophenAntipyresisElectron transport chainLipolysisMitochondriaNAPQI

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