The effect of 4-acetamidophenol on prostaglandin synthetase activity in bovine and ram seminal vesicle microsomes

Robak, J; Wiȩckowski, Andrzej; Gryglewski, R

doi:10.1016/0006-2952(78)90367-2

Cited by 56 publications

(18 citation statements)

References 13 publications

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“…Paracetamol also stimulated prostacyclin formation but unlike BW755C, was equally effective in both mucosal and forestomach homogenates, perhaps suggesting a different mechanism of action. In other studies, stimulation of prostaglandin synthetase by paracetamol in bovine and ram seminal vesicle preparations only occurred in the absence of cofactors, thus suggesting that paracetamol itself was acting as a cofactor (Robak, Wieckowski & Gryglewski, 1978) or perhaps as a free-radical scavenger.…”

Section: Discussionmentioning

confidence: 83%

“…For in vitro studies, some microsomal preparations have the disadvantage in requiring exogenous cofactors for efficient enzymatic conversion of exogenous arachidonic acid and these co-factors may alter drug effect (Robak et al, 1978) and distort the profile of products (Cottee, Flower, Moncada, Salmon & Vane, 1977). Tissue homogenates, which can generate prostacyclin and other prostaglandins from endogenous substrate, thus provide a simple, rapid and reproducible method for measuirng the effect of anti-inflammatory drugs on prostaglandin formation in vitro from gastro-intestinal and perhaps other tissues.…”

Section: Discussionmentioning

confidence: 99%

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Stimulation and inhibition of prostacyclin formation in the gastric mucosa and ileum in vitro by anti‐inflammatory agents

Boughton‐Smith

Whittle

1983

British J Pharmacology

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Homogenates of rat gastric mucosa, forestomach and ileum and dog gastric mucosa reproducibly generated prostacyclin from endogenous substrate. Prostacyclin formation was inhibited by pre‐incubation with indomethacin, flurbiprofen, naproxen, ketoprofen or meclofenamate (0.1–10 μm). BW755C (3‐amino‐1[m‐(trifluoromethyl)‐phenyl]‐2‐pyrazoline) stimulated prostacyclin production in the rat gastric mucosa and ileum with inhibition occurring only at high concentrations (>200 μm). The stimulation of prostacyclin production by BW755C in rat forestomach homogenates was less pronounced, with inhibition at concentrations > 20 μm. BW755C thus exhibits differential activity on prostacyclin production from different gastric tissues in vitro. The antioxidant‐lipoxygenase inhibitor, nordihydroguiaretic acid (NDGA, 3–15 μm) likewise augmented rat mucosal prostacyclin formation. Paracetamol stimulated and, at higher concentrations, inhibited prostacyclin formation (> 1 mm), and had comparable activity in both rat gastric tissues. The ability of NDGA and BW755C to enhance prostacyclin generation may reflect the removal of a modulating influence of lipoxygenase products on prostacyclin formation, the diversion of substrate to the cyclo‐oxygenase pathway, or free‐radical scavenging.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Stimulation and inhibition of prostacyclin formation in the gastric mucosa and ileum in vitro by anti‐inflammatory agents

Boughton‐Smith

Whittle

1983

British J Pharmacology

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“…The activity of acetaminophen in vitro also depends on the addition of cofactors. In the presence of glutathione and hydroquinone, acetaminophen inhibited COX activity of bull seminal vesicle microsomes but, in the absence of these cofactors, stimulated that of bovine and ram seminal vesicle microsomes (5). After the recognition of COX-1 and COX-2, by using cultured whole cells, acetaminophen demonstrated a low inhibitory potency for COX enzymes.…”

mentioning

confidence: 99%

Induction of an acetaminophen-sensitive cyclooxygenase with reduced sensitivity to nonsteroid antiinflammatory drugs

Simmons

Botting

Robertson

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

139

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The transformed monocyte͞macrophage cell line J774.2 undergoes apoptosis when treated for 48 h with competitive inhibitors of cyclooxygenase (COX) isoenzymes 1 and 2. Many of these nonsteroid antiinf lammatory drugs (NSAIDs), but in particular diclofenac, induce during this time period a COX activity that coincides with a robust induction of COX-2 protein. Induction of this activity requires high, apoptosis-inducing concentrations of diclofenac (>100 M). Prolonged treatment of J774.2 cells with lower doses of diclofenac inhibits COX activity, indicating that diclofenac is a time-dependent, pseudoirreversible inhibitor of COX-2. It is difficult to wash out the inhibition. However, the activity evoked by high concentrations of diclofenac has a profoundly distinct COX active site that allows diclofenac, its inducer, to be washed readily from its active site. The diclofenac-induced activity also has the unusual property of being more sensitive to inhibition by acetaminophen (IC 50 ‫؍‬ 0.1-1.0 mM) than COX-2 induced with bacterial lipopolysaccharide. Moreover, relative to COX-1 or COX-2, diclofenac-induced enzyme activity shows significantly reduced sensitivity to inhibition by diclofenac or other competitively acting nonsteroid antiinf lammatory drugs (NSAIDs) and the enzyme activity is insensitive to aspirin. If the robust induction of COX-2 observed is responsible for diclofenac-induced COX enzyme activity, it is clear that COX-2 can, therefore, exist in two catalytically active states. A luciferase reporter-construct that contains part of the COX-2 structure and binds into the membrane showed that chronic diclofenac treatment of fibroblasts results in marked mobilization of the fusion protein. Such a mobilization could result in enzymatically distinct COX-2 populations in response to chronic diclofenac treatment.The cloning of cyclooxygenase-2 (COX-2) in 1991 (1-3) explained many long-standing anomalies relating to the previous assumption of a single COX enzyme. However, not all of the problems have been solved by the characterization of two COX enzymes originating from different genes. One such problem is the effect of acetaminophen, which, unlike nonsteroid antiinflammatory drugs (NSAIDs), produces analgesia and antipyresis but has little effect on inflammation. The existence of additional COX enzymes was therefore postulated (4).Acetaminophen is a weak inhibitor of COX-1 and COX-2, which displays some selectivity toward COX enzymes from different organs. Thus, it is a more potent inhibitor of COX from dog and rabbit brain than that of dog spleen (4). The activity of acetaminophen in vitro also depends on the addition of cofactors. In the presence of glutathione and hydroquinone, acetaminophen inhibited COX activity of bull seminal vesicle microsomes but, in the absence of these cofactors, stimulated that of bovine and ram seminal vesicle microsomes (5). After the recognition of COX-1 and COX-2, by using cultured whole cells, acetaminophen demonstrated a low inhibitory potency for COX enzymes. Only IC 3...

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“…(2) (Lands et al, 1976;Robak et al, 1978; Lands Hertz & Cloarec, 1984), attempts were made to measure levels of lipid peroxides in the peritoneal cavity. However, a standard assay method failed to detect lipid peroxides, possibly because of rapid elimination as was demonstrated here and has been discussed by Salaris & Babbs (1988).…”

Section: Discussionmentioning

confidence: 99%

“…N-(4-hydroxyphenyl) acetamide (acetaminophen, paracetamol) also inhibits inflammatory pain but, despite extensive study, its mechanism of action remains obscure. For example, the effect of paracetamol on prostaglandin synthesis in the most widely used cellfree system (ram seminal vesicle microsomes) is highly dependent on experimental conditions: in the presence of high levels of lipid peroxides which inactivate the enzyme, paracetamol enhances prostaglandin synthesis; in the presence of low levels of lipid peroxides, paracetamol inhibits prostaglandin synthesis (Lands et al, 1976;Robak et al, 1978;Hertz & Cloarec, 1984). These results make it difficult to predict the in vivo effects of paracetamol on prostaglandin synthesis in a particular in vivo situation.…”

Section: Introductionmentioning

confidence: 99%

The antinociceptive activity of paracetamol in zymosan‐induced peritonitis in mice: the role of prostacyclin and reactive oxygen species

Doherty¹,

Beaver²,

Chan³

et al. 1990

British J Pharmacology

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1 Oral administration of high doses of paracetamol (600mg kg-1 or more) resulted in inhibition of the writhing and reduced the levels of prostacyclin (PGI2, measured as 6-keto-PGF1.) induced by intraperitoneal administration of zymosan in mice. The high oral doses of paracetamol required were accompanied by behavioural toxicity which may have contributed to the inhibition of writhing. 2 The number of writhes per mouse and the proportion of mice writhing at least once correlated significantly with the levels of 6-keto-PGF1,. However, inhibition of writhing by paracetamol occurred at higher levels of 6-keto-PGF1, than was previously observed with acidic non-steroidal anti-inflammatory agents.3 When injected i.p., PGI2, carbacyclin and iloprost (agonists at the PGI2 receptor) induced writhing. Intraperitoneal injection of PGI2 reversed the inhibition of writhing induced by indomethacin (1 mgkg-', p.o.) but not that induced by oral administration of paracetamol. 4 Paracetamol at 800mgkg-1, p.o., inhibited carbacyclin-induced writhing but indomethacin at lmgkg-1 p.o. did not. Paracetamol administered i.p. at 100mgkg-1 reduced the peritoneal levels of 6-keto-PGF1, and inhibited zymosan-induced but not carbacyclin-induced writhing and did not produce behavioural toxicity. 5The in vitro potency of paracetamol as a prostaglandin synthesis inhibitor is known to be reduced by the presence of lipid peroxides. However, no lipid peroxides, measured as thiobarbituric acid reactive material, were detected in the peritoneal lavage fluid of zymosan-injected mice. 6 Intraperitoneal administration of a mixture of superoxide dismutase and catalase reduced detectable superoxide anion by 98% without inhibiting the writhing response to zymosan or the antinociceptive potency of paracetamol. 7 The data are consistent with the suggestion that inhibition of PGI2 synthesis in the peritoneal cavity by paracetamol is responsible for only a part of its antinociceptive activity in this test. However, extremely high oral doses of paracetamol were required which produced behavioural toxicity which clearly contributed to the inhibition of writhing. The low potency of paracetamol in this model cannot be attributed to the generation of lipid peroxides via the oxidative burst.

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The effect of 4-acetamidophenol on prostaglandin synthetase activity in bovine and ram seminal vesicle microsomes

Cited by 56 publications

References 13 publications

Stimulation and inhibition of prostacyclin formation in the gastric mucosa and ileum in vitro by anti‐inflammatory agents

Stimulation and inhibition of prostacyclin formation in the gastric mucosa and ileum in vitro by anti‐inflammatory agents

Induction of an acetaminophen-sensitive cyclooxygenase with reduced sensitivity to nonsteroid antiinflammatory drugs

The antinociceptive activity of paracetamol in zymosan‐induced peritonitis in mice: the role of prostacyclin and reactive oxygen species

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