Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H
            <sub>2</sub>
            synthases

Boutaud, Olivier; Aronoff, David M.; Richardson, Jacob H.; Marnett, Lawrence J.; Oates, John A.

doi:10.1073/pnas.102588199

Cited by 207 publications

(216 citation statements)

References 57 publications

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“…Human blood was obtained following a protocol approved by the Institutional Review Board of Vanderbilt University. Washed platelets were prepared as described previously [17]. 12-Hydroperoxyeicosatetraenoic acid (12-HPETE), 12-hydroxyeicosatetraenoic acid (12-HETE), 5-phenyl-4-pentenyl hydroperoxide (PPHP) and 5-phenyl-4-pentenyl alcohol (PPA) were purchased from Cayman Chemicals (Ann Arbor, MI …”

Section: Methodsmentioning

confidence: 99%

“…Platelet-rich supernatant plasma was acidified to pH 6.4 with 0.15 M citric acid followed by centrifugation at 1,000 × g for 10 min at room temperature. The pellet was resuspended with 24.4 mM sodium phosphate buffer, pH 6.5/0.113 M NaCl/5.5 mM glucose and purified on a Sepharose 2B column equilibrated with the same buffer to obtain the washed platelets [17].…”

Section: Preparation Of Washed Plateletsmentioning

confidence: 99%

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Acetylation of prostaglandin H2 synthases by aspirin is inhibited by redox cycling of the peroxidase

Bala

Chin

Logan

et al. 2008

Biochemical Pharmacology

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Aspirin exerts its unique pharmacological effects by irreversibly acetylating a serine residue in the cyclooxygenase site of prostaglandin-H 2 -synthases (PGHSs). Despite the irreversibility of the inhibition, the potency of aspirin varies remarkably between cell types, suggesting that molecular determinants could contribute to cellular selectivity. Using purified enzymes, we found no evidence that aspirin is selective for either of the two PGHS isoforms, and we showed that hydroperoxide substrates of the PGHS peroxidase inhibited the rate of acetylation of PGHS-1 by 68%. Using PGHS-1 reconstituted with cobalt protoporphyrin, a heme devoid of peroxidase activity, we demonstrated that reversal by hydroperoxides of the aspirin-mediated acetylation depends upon the catalytic activity of the PGHS peroxidase. We demonstrated that inhibition of PGHS-2 by aspirin in cells in culture is reversed by 12-hydroperoxyeicosatetraenoic acid dose-dependently (ED 50 = 0.58 ± 0.15 μM) and that in cells with high levels of hydroperoxy-fatty acids (RAW264.7) the efficacy of aspirin is markedly decreased as compared to cells with low levels of hydroperoxides (A549; IC 50 s = 256 ± 22 μM and 11.0 ± 0.9 μM, respectively). Together, these findings indicate that acetylation of the PGHSs by aspirin is regulated by the catalytic activity of the peroxidase which yields a higher oxidative state of the enzyme.

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Section: Methodsmentioning

confidence: 99%

Section: Preparation Of Washed Plateletsmentioning

confidence: 99%

Acetylation of prostaglandin H2 synthases by aspirin is inhibited by redox cycling of the peroxidase

Bala

Chin

Logan

et al. 2008

Biochemical Pharmacology

Self Cite

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“…When administered to humans, acetaminophen reduces levels of prostaglandin metabolites in urine but does not reduce synthesis of prostaglandins by blood platelets or by the gastric mucosa (21,22). It has been shown that the cellular selectivity of acetaminophen's capacity to inhibit COX activity is determined by the differential production of hydroperoxide by cells (23). As an example, 12-hydroperoxyeicosatetraenoic acid, a major product of the platelet, completely reverses the action of acetaminophen on COX-1 (23).…”

Section: Is Acetaminophen Just Another Cox Inhibitor?mentioning

confidence: 99%

“…It has been shown that the cellular selectivity of acetaminophen's capacity to inhibit COX activity is determined by the differential production of hydroperoxide by cells (23). As an example, 12-hydroperoxyeicosatetraenoic acid, a major product of the platelet, completely reverses the action of acetaminophen on COX-1 (23). The results are consistent with a mechanism of action of acetaminophen in which COX inhibition is more effective under conditions of low peroxide concentration, and this variability could account for the tissue selectivity of acetaminophen (24).…”

Section: Is Acetaminophen Just Another Cox Inhibitor?mentioning

confidence: 99%

Et tu, acetaminophen?

Abramson¹

2002

Arthritis & Rheumatism

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“…1 Despite its widespread use, the mechanisms that mediate the analgesic and antipyretic effects of APAP are not entirely understood. Although in vitro studies have demonstrated an ability of APAP to inhibit cyclooxygenase-1 and -2 (COX-1 and -2), 2,3 its weak anti-inflammatory activity as compared with that of non-steroidal anti-inflammatory drugs (NSAIDs) suggests that other non-COX-related mechanisms also are involved. [4][5][6] More recently, the pharmacological effects of APAP have been suggested to be related to the formation of a metabolite (AM404, Fig.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and in vivo evaluation of non-hepatotoxic acetaminophen analogs

Vaccarino

Paúl

Mukherjee

et al. 2007

Bioorganic & Medicinal Chemistry

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Abstract-A series of acetaminophen (APAP) analogs, 2-(1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)-N-(4-hydroxyphenyl)alkanecarboxamides, bearing a heterocyclic moiety linked to the p-acylaminophenol fragment, were prepared in a general project to develop APAP analogs with modulated pharmacokinetic profiles. Unexpectedly, the products described maintained the in vivo analgesic profile, while the characteristic hepatotoxicity of APAP was consistently reduced. One of the products, 5a, was studied in vivo in comparison with APAP. Compound 5a displayed an analgesic efficacy comparable to that of APAP. A relatively high acute oral dose of 5a (6 mmol/kg) produced no measurable toxicity, whereas the equimolar dose of APAP increased transaminase activity, depleted hepatic and renal glutathione, and resulted in mortality. In human hepatocytes (HEPG-2) and in human primary cultures of normal liver cells, APAP, but not 5a, was associated with apoptotic cell death, Fas-ligand up-regulation, and CAR (constitutive androstane receptor) activation, contributing to a favorable safety profile of 5a as an orally delivered analgesic.

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

Cited by 207 publications

References 57 publications

Acetylation of prostaglandin H2 synthases by aspirin is inhibited by redox cycling of the peroxidase

Acetylation of prostaglandin H2 synthases by aspirin is inhibited by redox cycling of the peroxidase

Et tu, acetaminophen?

Synthesis and in vivo evaluation of non-hepatotoxic acetaminophen analogs

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

Cited by 207 publications

References 57 publications

Acetylation of prostaglandin H2 synthases by aspirin is inhibited by redox cycling of the peroxidase

Acetylation of prostaglandin H2 synthases by aspirin is inhibited by redox cycling of the peroxidase

Et tu, acetaminophen?

Synthesis and in vivo evaluation of non-hepatotoxic acetaminophen analogs

Contact Info

Product

Resources

About

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