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

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 meta-bolism 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 con-sumption 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 mu M) 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 an-tipyretics 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.

Automated summary

The research findings indicate that the inhibition of mitochondrial function may be the key to the antipyretic and hypothermic properties of acetaminophen. By suppressing fatty acid uptake and oxidation, acetaminophen reduces mitochondrial function and subsequently lowers body temperature. These findings offer new insights for the development of new antipyretic drugs.