Inhibition of lipolysis: A novel explanation for the hypothermic actions of acetaminophen in non-febrile rodents.
Acetaminophen is both widely used to treat children with fever and is also responsible for thousands being hospitalised annually. Historically the antipyretic actions of acetaminophen were attributed to the inhibition of cyclooxygenase (COX-1/2) enzymes and more recently a novel COX-1 variant (COX-3) located in the brain. However, the evidence for acetaminophen-mediated COX inhibition remains contentious. This study assesses the impact of acetaminophen and other putative COX-3 inhibitors on the release of fatty acids during lipolysis as an alternative mechanism by which antipyretics can reduce body temperature during fever. 3T3-L1 adipocytes, primary brown adipocytes and isolated mitochondria were exposed to COX-3 inhibitors and lipolysis and mitochondrial electron transport chain function assessed. Acetaminophen, aminopyrine and antipyrine at 1-10 mM caused a significant decrease (up to 70%; P < 0.01, from control) in lipolysis within 1, 3 and 24 h without affecting cell viability. The inhibition was observed regardless of where along its signalling pathway lipolysis was stimulated. All three compounds were found to significantly attenuate mitochondrial function by up to 30% for complex I and 40% for complex II (P < 0.01, from control). These novel observations combined with the known limited inhibition of the COX enzymes by acetaminophen suggest both the antipyretic and hypothermia induced by acetaminophen and related compounds could be attributed to the direct inhibition of lipolysis and mitochondrial function, rather than cyclooxygenase inhibition centrally. Further these observations could provide new drug targets for reducing fever with the added bonus of fewer individuals being hospitalized by accidental acetaminophen overdose.
['Bashir|Shazma|S|', 'Elegunde|Busayo|B|', 'Morgan|Winston A|WA|']
D041721:3T3-L1 Cells D015124:8-Bromo Cyclic Adenosine Monophosphate D000082:Acetaminophen D017667:Adipocytes D000318:Adrenergic beta-Agonists D000632:Aminopyrine D000818:Animals D058633:Antipyretics D000983:Antipyrine D001831:Body Temperature D002454:Cell Differentiation D005576:Colforsin D007545:Isoproterenol D008066:Lipolysis D051379:Mice D051381:Rats D017208:Rats, Wistar
Lipolysis Acetaminophen Cyclooxygenase Mitochondria Electron transport chain Hypothermia