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Acetaminophen-Induced Hypothermia in Mice Is Mediated by a Prostaglandin Endoperoxide Synthase 1 Gene-Derived Protein
Samir S. Ayoub, Regina M. Botting, Sarita Goorha, Paul R. Colville-Nash, Derek A. Willoughby, Leslie R. Ballou and John R. Vane
Proceedings of the National Academy of Sciences of the United States of America
Vol. 101, No. 30 (Jul. 27, 2004), pp. 11165-11169
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/3372870
Page Count: 5
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Acetaminophen is a widely used antipyretic analgesic, reducing fever caused by bacterial and viral infections and by clinical trauma such as cancer or stroke. In rare cases in humans, e.g., in febrile children or HIV or stroke patients, acetaminophen causes hypothermia while therapeutic blood levels of the drug are maintained. In C57/BL6 mice, acetaminophen caused hypothermia that was dose related and maximum (>2°C below normal) with a dose of 300 mg/kg. The reduction and recovery of body temperature was paralleled by a fall of >90% and a subsequent rise of prostaglandin ( PG) E2 concentrations in the brain. In cyclooxygenase ( COX)-2-/- mice, acetaminophen (300 mg/kg) produced hypothermia accompanied by a reduction in brain PGE2 levels, whereas in COX-1-/- mice, the hypothermia to this dose of acetaminophen was attenuated. The brains of COX-1-/- mice had ≈70% lower levels of PGE2 than those of WT animals, and these levels were not reduced further by acetaminophen. The putative selective COX-3 inhibitors antipyrine and aminopyrine also reduced basal body temperature and brain PGE2 levels in normal mice. We propose that acetaminophen is a selective inhibitor of a COX-1 variant and this enzyme is involved in the continual synthesis of PGE2 that maintains a normal body temperature. Thus, acetaminophen reduces basal body temperature below normal in mice most likely by inhibiting COX-3.
Proceedings of the National Academy of Sciences of the United States of America © 2004 National Academy of Sciences