Inhibitors of cytochrome P-450-dependent arachidonic acid metabolism

Capdevila, Jorge H.; Gil, Lionel; Orellana, Miriam; Marnett, Lawrence J.; Mason, J. Ian; Yadagiri, Pendri; Falck, J. R.

doi:10.1016/0003-9861(88)90340-2

Cited by 190 publications

(101 citation statements)

References 13 publications

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“…Thus we tested two cytochrome P-450 inhibitors (clotrimazole and SKF 525A), and ETYA which inhibits arachidonic acid metabolism via cyclooxygenase, lipoxygenase and cytochrome P-450 monooxygenase (Pinto et al, 1987;Capdevila et al, 1988). The results shown in Table 3 do not support the participation of the cytochrome P-450 products in the hypercapnia-produced vasodilation.…”

Section: Discussionmentioning

confidence: 95%

Involvement of barium‐sensitive K⁺ channels in endothelium‐dependent vasodilation produced by hypercapnia in rat mesenteric vascular beds

Okazaki

Endou

Okumura

1998

British J Pharmacology

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1 We examined the vasodilatory e ect of hypercapnia in the rat isolated mesenteric vascular bed. The preparation was perfused constantly (5 ml min 71 with oxygenated Krebs-Ringer solution, and the perfusion pressure was measured. In order to keep the extracellular pH (pHe) constant (around 7.35) against a change in CO 2 , adequate amounts of NaHCO 3 were added to Krebs-Ringer solution. 2 In the endothelium intact preparations, an increase in CO 2 from 2.5% to 10% in increments of 2.5% decreased the 10 mM phenylephrine (PE)-produced increase in the perfusion pressure in a concentrationdependent manner. Denudation of the endothelium by CHAPS (3-[(3-cholamidopropyl)-dimethylammonio]-l-propanesulphonate) (5 mg l 71 , 90 s perfusion) abolished the vasodilatory e ect of hypercapnia. 3 An increase in CO 2 from 5% to 10% reduced the increases in the perfusion pressure produced by 10 mM PE and 400 nM U-46619 by 48% and 44%, respectively. N G -monomethyl-L-arginine (100 mM) and indomethacin (10 mM) did not a ect the vasodilatory e ect of hypercapnia, whereas the vasodilatory response of the preparation to hypercapnia disappeared when the preparation was contracted by 60 mM K + instead of PE or U-46619. 4 The vasodilatory e ect of hypercapnia observed in the PE-or U-46619-precontracted preparation was a ected by neither tetraethylammonium (1 mM), apamin (500 mM), glibenclamide (10 mM), nor 4-aminopyridine (1.5 mM). On the other hand, pretreatment with Ba 2+ at a concentration of 0.3 mM abolished the hypercapnia-produced vasodilation. 5 An increase in the concentration of K + in Krebs-Ringer solution from 4.5 mM to 12.5 mM in increments of 2 mM reduced the PE-produced increase in the perfusion pressure in a concentrationdependent manner. Pretreatment of the preparations with not only Ba 2+ (0.3 mM) but also CHAPS abolished the vasodilatory e ect of K + . 6 The results suggest that an increase in CO 2 produces vasodilation by an endothelium-dependent mechanism in the rat mesenteric vascular bed. The membrane hyperpolarization of the endothelial cell by an activation of the inward recti®er K + channel seems to be the mechanism underlying the hypercapnia-produced vasodilation. Neither nitric oxide nor prostaglandins are involved in this response.

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Section: Discussionmentioning

confidence: 95%

Involvement of barium‐sensitive K⁺ channels in endothelium‐dependent vasodilation produced by hypercapnia in rat mesenteric vascular beds

Okazaki

Endou

Okumura

1998

British J Pharmacology

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“…However, nitric oxide synthase, a heme thiolate enzyme related to cytochrome P450, is reported to be inhibited by aspirin and related NSAIDs (7). Indomethacin can also inhibit at least one classical P450 monooxygenase that is involved in arachidonic acid metabolism (43,44). Thus NSAIDs such as aspirin, which are known to disrupt the arachidonic cascade, may do so by affecting enzymes other than PGHS (43).…”

Section: Resultsmentioning

confidence: 99%

Aspirin Inhibition and Acetylation of the Plant Cytochrome P450, Allene Oxide Synthase, Resembles that of Animal Prostaglandin Endoperoxide H Synthase

Pan

Camara

Gardner

et al. 1998

Journal of Biological Chemistry

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The enzymatic reactions leading to octadecanoid lipid signaling intermediates in plants are similar to those of animals and are inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs) such as salicylic acid and aspirin. In animals, NSAIDs inhibit the cyclooxygenase (COX) activity of prostaglandin endoperoxide H synthase, which ultimately blocks the formation of prostaglandins. In plants, NSAIDs block the formation of 12-oxophytodienoic acid and jasmonates, which are the equivalent signaling compounds. In this study we show that NSAIDs act as competitive inhibitors of allene oxide synthase (AOS), the cytochrome P450 that initiates plant oxylipin synthesis. We also show that aspirin causes the time-dependent inhibition and acetylation of AOS, which leads the irreversible inactivation of this enzyme. This inhibition and acetylation superficially resembles that observed for the inactivation of COX in animals. In AOS, aspirin acetylates three serine residues near the C-terminal region that appear to be highly conserved among AOS sequences from other plants but are not conserved among "classical" type P450s. The role of these serine residues is unclear. Unlike animal COX, where acetylation of a single serine residue within the substrate channel leads to inactivation of prostaglandin endoperoxide H synthase, the three serine residues in AOS are not thought to line the putative substrate channel. Thus, inhibition by aspirin may be by a different mechanism. It is possible that aspirin and related NSAIDs could inhibit other P450s that have motifs similar to AOS and consequently serve as potential biochemical targets for this class of drugs.

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“…The monooxygenase-dependent production of ROS in liver microsomes, supported by NADPH, is a well-known phenomenon (Gillette et al, 1957) that clearly contributes to the total cellular production of reactive oxygen in rat liver, without necessitating enzyme induction (Bondy et al, 1994). Even in the absence of exogenous xenobiotic substrates, endogenous substrates, such as any one of the many arachidonic acid metabolites, may stimulate ROS production (Capdevila et al, 1988;Rifkind et al, 1990;Nakai et al, 1992). In this regard, lipoxin A4, a metabolite of arachidonic acid, may act as an inducing ligand for the AHR (Schaldach et al, 1999).…”

Section: Role Of Cytochrome P450 Enzymes In Tcdd Toxicitymentioning

confidence: 99%

Induction of Oxidative Stress Responses by Dioxin and other Ligands of the Aryl Hydrocarbon Receptor

et al. 2005

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ᮀTCDD and other polyhalogenated aromatic hydrocarbon ligands of the aryl hydrocarbon receptor (AHR) have been classically considered as non-genotoxic compounds because they fail to be directly mutagenic in either bacteria or most in vitro assay systems. They do so in spite of having repeatedly been linked to oxidative stress and to mutagenic and carcinogenic outcomes. Oxidative stress, on the other hand, has been used as a marker for the toxicity of dioxin and its congeners. We have focused this review on the connection between oxidative stress induction and the toxic effects of fetal and adult dioxin exposure, with emphasis on the large species difference in sensitivity to this agent. We examine the roles that the dioxin-inducible cytochromes P450s play in the cellular and toxicological consequences of dioxin exposure with emphasis on oxidative stress involvement. Many components of the health consequences resulting from dioxin exposure may be attributable to epigenetic mechanisms arising from prolonged reactive oxygen generation.

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Inhibitors of cytochrome P-450-dependent arachidonic acid metabolism

Cited by 190 publications

References 13 publications

Involvement of barium‐sensitive K⁺ channels in endothelium‐dependent vasodilation produced by hypercapnia in rat mesenteric vascular beds

Involvement of barium‐sensitive K⁺ channels in endothelium‐dependent vasodilation produced by hypercapnia in rat mesenteric vascular beds

Aspirin Inhibition and Acetylation of the Plant Cytochrome P450, Allene Oxide Synthase, Resembles that of Animal Prostaglandin Endoperoxide H Synthase

Induction of Oxidative Stress Responses by Dioxin and other Ligands of the Aryl Hydrocarbon Receptor

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Inhibitors of cytochrome P-450-dependent arachidonic acid metabolism

Cited by 190 publications

References 13 publications

Involvement of barium‐sensitive K+ channels in endothelium‐dependent vasodilation produced by hypercapnia in rat mesenteric vascular beds

Involvement of barium‐sensitive K+ channels in endothelium‐dependent vasodilation produced by hypercapnia in rat mesenteric vascular beds

Aspirin Inhibition and Acetylation of the Plant Cytochrome P450, Allene Oxide Synthase, Resembles that of Animal Prostaglandin Endoperoxide H Synthase

Induction of Oxidative Stress Responses by Dioxin and other Ligands of the Aryl Hydrocarbon Receptor

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Involvement of barium‐sensitive K⁺ channels in endothelium‐dependent vasodilation produced by hypercapnia in rat mesenteric vascular beds

Involvement of barium‐sensitive K⁺ channels in endothelium‐dependent vasodilation produced by hypercapnia in rat mesenteric vascular beds