What is the clinical evidence from this study?

Study design: Other. Intervention: Acetaminophen vs. Control (no acetaminophen). Primary outcome: Inhibition of PGHS activity (IC50) with 2 µM arachidonic acid (IC50 4.3 µM in HUVECs vs 1,870 µM in platelets).

May 14, 2002Proceedings of the National Academy of Sciences212 citationsOpen Access

Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H 2 synthases

OBOlivier BoutaudVanderbilt University DADavid M. AronoffIndiana University Health JRJacob H. RichardsonVanderbilt University

Key Result

Acetaminophen selectively inhibits prostaglandin H2 synthase activity in endothelial cells (IC50 4.3 µM) compared to platelets (IC50 1,870 µM), with cellular selectivity driven by hydroperoxide concentrations.

PICO

Population

In vitro study using human umbilical vein endothelial cells, human platelets, and purified enzymes to investigate the cellular specificity of acetaminophen.

Intervention / Comparator

Acetaminophen vs Control (no acetaminophen) (Various concentrations (e.g., 4.3 µM to 3.3 mM))

Primary Outcome

Inhibition of PGHS activity (IC50) with 2 µM arachidonic acid — IC50 4.3 µM in HUVECs vs 1,870 µM in platelets

Main Result

Effect estimate: IC50 4.3 µM in HUVECs vs 1,870 µM in platelets

Limitations

In vitro study design

Abstract

Acetaminophen has antipyretic and analgesic properties yet differs from the nonsteroidal antiinflammatory drugs and inhibitors of prostaglandin H synthase (PGHS)-2 by exhibiting little effect on platelets or inflammation. We find parallel selectivity at a cellular level; acetaminophen inhibits PGHS activity with an IC(50) of 4.3 microM in interleukin (IL)-1 alpha-stimulated human umbilical vein endothelial cells, in contrast with an IC(50) of 1,870 microM for the platelet, with 2 microM arachidonic acid as substrate. This difference is not caused by isoform selectivity, because acetaminophen inhibits purified ovine PGHS-1 and murine recombinant PGHS-2 equally. We explored the hypothesis that this difference in cellular responsiveness results from antagonism of the reductant action of acetaminophen on the PGHSs by cellular peroxides. Increasing the peroxide product of the PGHS-cyclooxygenase, prostaglandin G(2) (PGG(2)), by elevating the concentration of either enzyme or substrate reverses the inhibitory action of acetaminophen, as does the addition of PGG(2) itself. 12-Hydroperoxyeicosatetraenoic acid (0.3 microM), a major product of the platelet, completely reverses the action of acetaminophen on PGHS-1. Inhibition of PGHS activity by acetaminophen in human umbilical vein endothelial cells is abrogated by t-butyl hydroperoxide. Together these findings support the hypothesis that the clinical action of acetaminophen is mediated by inhibition of PGHS activity, and that hydroperoxide concentration contributes to its cellular selectivity.

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