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

Article


Bashir, S. and Morgan, W. 2022. Inhibition of mitochondrial function: An alternative explanation for the antipyretic and hypothermic actions of acetaminophen. Life Sciences. 312 (Art. 121194). https://doi.org/10.1016/j.lfs.2022.121194
AuthorsBashir, S. and Morgan, W.
Abstract

Aims

Acetaminophen is the medication of choice when treating fever because of its limited anti-inflammatory effects. However at overdose it can cause mitochondrial dysfunction and damage, often associated with metabolism to N-acetyl-p-benzoquinone imine (NAPQI). What has never been investigated is whether the inhibition of mitochondrial function, particularly fatty acid uptake and oxidation could be the key to its antipyretic and hypothermic properties.

Methods

Mitochondrial function and fatty acid oxidation (FAO) was determined by measuring oxygen consumption rate (OCR) in isolated mitochondria and in 3T3-L1 adipocytes using the XFp Analyser. Basal fatty acids and adrenergic stimulated OCR of mitochondria and 3T3-L1 adipocytes were assessed with acetaminophen and compared to NAPQI, etomoxir, and various mitochondrial stress compounds.

Key findings

Using the XFp Analyser, acetaminophen (10 mM) decreased FAO by 31 % and 29 % in basal and palmitate stimulated adipocytes. NAPQI (50 μM) caused a 63 % decrease in both basal and palmitate stimulated FAO. Acetaminophen (10 mM) caused a 34 % reduction in basal and adrenergic stimulated OCR. In addition acetaminophen also inhibited complex I and II activity at 5 mM. NAPQI was far more potent at reducing mitochondrial respiratory capacity, maximum respiratory rates and ATP production than acetaminophen.

Significance

These studies demonstrate the direct inhibition of mitochondrial function by acetaminophen at concentrations which have been shown to reduce fever and hypothermia in mammals. Understanding how antipyretics directly affect mitochondrial function and heat generation could lead to the development of new antipyretics which are not compromised by the anti-inflammatory and toxicity of the current medications.

JournalLife Sciences
Journal citation312 (Art. 121194)
ISSN0024-3205
Year2022
PublisherElsevier
Accepted author manuscript
License
File Access Level
Anyone
Digital Object Identifier (DOI)https://doi.org/10.1016/j.lfs.2022.121194
Publication dates
Online12 Nov 2022
Publication process dates
Accepted10 Nov 2022
Deposited01 Dec 2022
Copyright holder© 2022 Elsevier
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