Proceedings of The Physiological Society

Mitochondria: Form and function (London, UK) (2017) Proc Physiol Soc 38, PC13

Poster Communications

Title: Mitochondrial oxygen consumption a new target for paracetamol?

S. Bashir1, S. AYOUB1, W. MORGAN1


Paracetamol has been known for some time to reduce core body temperature of both febrile and non-febrile animals by a mechanism that is not fully understood. Historically the actions of paracetamol were attributed to the inhibition of central cyclo-oxygenase enzymes however given the weak inhibitory effects on COX-1 and COX-2 enzymes alternative targets have been sought including a possible novel COX-3. Both reduction of pyresis and hypothermia occurs only when metabolic rate (heat production) decreases and/or heat loss increases. In an attempt to determine if the hypothermic properties of paracetamol could be attributed to the impact on mitochondrial energy metabolism, studies were undertaken to assess the effect of paracetamol and two COX-3 inhibitors aminophenazone and phenazone on mitochondrial oxygen consumption in both 3T3-L1 mouse adipocytes and isolated mitochondria. 3T3-L1 adipocytes were seeded in XFp microplates and oxygen consumption rate (OCR) was measured using Seahorse XFp Analyser. At concentrations (5-10mM) known to cause hypothermia and antipyresis paracetamol, aminophenazone and phenazone cause a significant (up to 50%) inhibition of oxygen consumption in 3T3-L1 cells without affecting cell viability. Isolated rat liver mitochondria were plated in XFp microplates and then transferred to the Seahorse XFp Analyser. Using electron flow assay, paracetamol (10mM) was also able to inhibit oxygen consumption in a manner similar to known inhibitors of the electron transport chain rotenone and antimycin A. Both the maintenance of normal body temperature and the induction of pyresis require increased mitochondrial electron transport chain activity and associated oxygen consumption. The failure to find a central target for the hypothermic effects of paracetamol and ability of paracetamol and other hypothermic agents to inhibit oxygen consumption without a loss of cellular viability suggest that disruption of mitochondrial oxygen consumption observed in differentiated adipocytes and isolated mitochondria could partly explain the hypothermic properties of paracetamol and similar compounds.

Where applicable, experiments conform with Society ethical requirements