Acetaminophen-induced hypothermia in mice is mediated by a prostaglandin endoperoxide synthase 1 gene-derived protein

Abstract

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 degrees 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)E(2) concentrations in the brain. In cyclooxygenase (COX)-2(-/-) mice, acetaminophen (300 mg/kg) produced hypothermia accompanied by a reduction in brain PGE(2) levels, whereas in COX-1(-/-) mice, the hypothermia to this dose of acetaminophen was attenuated. The brains of COX-1(-/-) mice had approximately 70% lower levels of PGE(2) 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 PGE(2) 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 PGE(2) that maintains a normal body temperature. Thus, acetaminophen reduces basal body temperature below normal in mice most likely by inhibiting COX-3.

Fig. 1.

The effect of increasing doses of acetaminophen (Apap) on body temperature in male C57/BL6 mice. A dose-related fall in temperature was obtained with 100–300 mg/kg acetaminophen with a maximum effect at 300 mg/kg; n = 3.

Fig. 2.

Time course of the hypothermic effect of 300 mg/kg acetaminophen (Apap) i.p. in male C57/BL6 mice compared with 100 mg/kg antipyrine, 50 mg/kg aminopyrine, and vehicle control; n = 3–5.

Fig. 3.

The effect of 300 mg/kg acetaminophen i.p. on basal body temperature and brain PGE₂ levels in male C57/BL6 mice. Brains were removed for PGE₂ determinations at intervals for 4 h after administration of acetaminophen. Body temperature and brain PGE₂ were reduced in parallel and recovered together. □, Body temperature; histograms represent brain PGE₂; n = 6.

Fig. 4.

The hypothermic response to 300 mg/kg acetaminophen (Apap) i.p. in COX-1 KO mice and COX-2 KO mice. Deletion of Ptgs1 reduced (A), whereas deletion of Ptgs2 had no effect on (B) the hypothermic action of acetaminophen; n = 3–6.

Fig. 5.

The effect of 300 mg/kg acetaminophen (Apap) on brain PGE₂ levels in COX-1 KO and COX-2 KO mice. Brains of COX-1 KO mice (A) and COX-2 KO mice (B) were removed and frozen 1 h after administration of acetaminophen to male or female animals. Acetaminophen reduced PGE₂ in WT and KO mice except Ptgs1^–/–. Control PGE₂ levels in Ptgs1^–/– animals were ≈30% of those in WT; n = 4–7; n.s., not significant.

Fig. 6.

Expression of COX-1, COX-2, and COX-3 mRNA in brain tissues of COX-2 KO mice.