Pefabloc, 4-[2-aminoethyl]benzenesulfonyl fluoride, is a new, potent nontoxic and irreversible inhibitor of PAF-degrading acetylhydrolase

Dentan, Christine; Tselepis, Alexandros D.; Chapman, M. John; Ninio, Ewa

doi:10.1016/0005-2760(95)00226-x

Cited by 75 publications

(54 citation statements)

References 20 publications

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“…21,22 In the present study, Pefabloc inhibited the increased PAF-AH activity in plasma by nearly 97% and had little effect on plasma LCAT activity ( Table 1). The increased bile PAF-AH activity in response to LPS was inhibited by 72% with Pefabloc.…”

Section: Pharmacological Characteristics Of Bile and Plasma Paf-ah Ansupporting

confidence: 49%

“…35 Differential inhibition of plasma PAF-AH and LCAT by Pefabloc and DFP, both serine protease inhibitors, very probably reflects the distinct hydrophobicity of the active center environments of these enzymes. 21,22 The much less hydrophobic Pefabloc completely inhibited plasma PAF-AH suggesting a low hydrophobicity of the enzyme' s catalytic center, whereas the catalytic center of LCAT may be much more hydrophobic rendering it less easily accessible to low concentrations of Pefabloc. It has been shown that Pefabloc and DFP inhibit plasma and intracellular type PAF-AH to a similar extent, 22 indicating that susceptibility to these inhibitors depends on the presence and availability of the serine residue in the active center of the enzyme that is common for all types of PAF-acetyhydrolases.…”

Section: Discussionmentioning

confidence: 99%

“…PAF-AH (both the plasma type and intracellular enzyme) and LCAT are serine-dependent enzymes and are inhibited by serine protease inhibitors. 1,21,22 However, be-cause of their different hydrophobicity, human plasma LCAT and PAF-AH possess quite distinct sensitivities to various serine protease inhibitors such as diisopropylfluoro phosphate (DFP) and Pefabloc [4-(2-aminoethyl)-benzenesulfonyl fluoride hydrochloride]. At low concentrations, Pefabloc selectively inhibits human and rat plasma and intracellular PAF-AH but not LCAT, whereas DFP decreases LCAT activity by 90% but does not affect PAF-AH.…”

mentioning

confidence: 99%

“…At low concentrations, Pefabloc selectively inhibits human and rat plasma and intracellular PAF-AH but not LCAT, whereas DFP decreases LCAT activity by 90% but does not affect PAF-AH. 21,22 PAF-AH circulating in plasma, predominantly associated with low-density lipoproteins, may play a major role in the prevention of both systemic and local inflammatory effects of PAF and oxidized phospholipids. Elstad et al 23 showed that human blood monocytes secrete large amounts of PAF-AH undistinguishable from the plasma type enzyme during maturation to macrophages in culture, implicating macrophages as a major source of this enzyme in the circulation.…”

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confidence: 99%

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Hepatic regulation of platelet-activating factor acetylhydrolase and lecithin: Cholesterol acyltransferase biliary and plasma output in rats exposed to bacterial lipopolysaccharide

et al. 1999

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Normal rat bile contains secretory platelet-activating factor acetylhydrolase (PAF-AH), the enzyme capable of hydrolyzing the inflammatory mediator platelet-activating factor (PAF), and phospholipids containing oxidized truncated fatty acids. Because lecithin:cholesterol acyltransferase (LCAT) possesses intrinsic PAF-AH-like activity, it also may represent a potential anti-inflammatory enzyme. The behavior of PAF-AH and LCAT in hepatobiliary inflammatory responses in vivo has not been characterized. We therefore investigated the biliary and plasma secretion and pharmacological characteristics of these enzymes in rats subjected to intraportal bacterial endotoxin exposure (lipopolysaccharide [LPS], Escherichia coli, 055:B5). Portal vein LPS infusion (1 mg/kg, bolus) resulted in a maximal 4-to 5-fold increase in bile PAF-AH-specific activity with a gradual decline to baseline by 18 hours. Biliary PAF-AH hydrolyzed also the truncated sn-2-succinoyl and sn-2-glutaroyl analogs of PAF, indicating a broader activity of PAF-AH in bile toward byproducts of glycerophospholipid peroxidation. Plasma PAF-AH activity was not altered 5 hours after LPS injection compared with saline injection, but it was significantly elevated 18 hours after endotoxin exposure. The levels of LCAT in bile were low and declined to nearly undetectable values by 5 hours after cannulation in both control and LPS-exposed rats. Plasma LCAT activity was significantly increased after 5 hours and decreased 18 hours after LPS injection. In summary, hepatic exposure to endotoxin results in a rapid increase in biliary secretion of PAF-AH followed by elevation of LCAT and PAF-AH levels in plasma. We propose that biliary secretion of PAF-AH may be involved in the hepatic response to endotoxic insult by counteracting potential inflammatory damage in the biliary tree and gastrointestinal tract, whereas plasma increases in LCAT and PAF-AH may promote elimination of excess PAF and oxidized phospholipids in the circulation. (HEPATOLOGY 1999;30:128-136.)

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Section: Pharmacological Characteristics Of Bile and Plasma Paf-ah Ansupporting

confidence: 49%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Hepatic regulation of platelet-activating factor acetylhydrolase and lecithin: Cholesterol acyltransferase biliary and plasma output in rats exposed to bacterial lipopolysaccharide

et al. 1999

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“…Lecithin-:cholesterol acyltransferase activity was very low and equal in both LDL fractions (0.03Ϯ0.01 nmol · h Ϫ1 · mL Ϫ1 ). Preincubation of both LDL fractions with Pefabloc 500 mol/L (Sigma), a known specific inhibitor of PAF-AH, 16 abolished the hydrolyzing activity of PAF-AH by up to 90% (Table 2), which indicates that hydrolysis of thio-PAF was specific for PAF-AH.…”

Section: Resultsmentioning

confidence: 98%

Platelet-Activating Factor Acetylhydrolase Is Mainly Associated With Electronegative Low-Density Lipoprotein Subfraction

et al. 2003

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Background-Electronegative LDL [LDL(Ϫ)], a modified subfraction of LDL present in plasma, induces the release of interleukin-8 and monocyte chemotactic protein-1 from cultured endothelial cells. Methods and Results-We demonstrate that platelet-activating factor acetylhydrolase (PAF-AH) is mainly associated with LDL(Ϫ). LDL(Ϫ) had 5-fold higher PAF-AH activity than the nonelectronegative LDL subfraction [LDL(ϩ)] in both normolipemic and familial hypercholesterolemic subjects. Western blot analysis after SDS-PAGE confirmed these results, because a single band of 44 kDa corresponding to PAF-AH appeared in LDL(Ϫ) but not in LDL(ϩ).Nondenaturing polyacrylamide gradient gel electrophoresis demonstrated that PAF-AH was bound to LDL(Ϫ) regardless of LDL size. In accordance with the above findings, nonesterified fatty acids, a cleavage product of PAF-AH, were increased in LDL(Ϫ) compared with LDL(ϩ). Conclusions-The

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Analysis of oxidized glycerophosphocholine lipids using electrospray ionization mass spectrometry and microderivatization techniques

et al. 2000

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Oxidized low‐density lipoprotein (LDL) is thought to play an important role in atherogenesis and cardiovascular disease in humans. Oxidized LDL is a complex mixture of many oxidized species, including numerous oxidized glycerophospholipids. Electrospray ionization and tandem mass spectrometry as well as microchemical derivatization of high‐performance liquid chromatographically purified fractions derived from oxidized LDL were investigated as means to determine the structure of individual components present in oxidized LDL. One major oxidized phosphocholine lipid had an [M + H]+ ion at m/z 650. Derivatization to the trimethylsilyl ether and methoxime caused shifts in mass which, along with negative ion collision‐induced dissociation mass spectra, were consistent with the presence of three species, 1‐palmitoyl‐2‐(9‐oxononanoyl)glycerophosphocholine and two isomeric 1‐octadecanoyl‐2‐(hydroxyheptenoyl)glycerophosphocholines. These species were chemically synthesized. Trimethylsilylation of free hydroxyl groups increased the mass of the phospholipid acyl chains containing hydroxyl groups by 72 u. Conversion of carbonyl groups to the methoxylamine derivative increased the mass by 29 u. Ozonolysis of those products which contained double bonds proved to be a facile technique to determine the position and number of double bonds present. The use of these techniques was illustrated in the structural characterization of one major component (m/z 650, positive ions) in oxidized LDL as 1‐octadecanoyl‐2‐(7‐hydroxyhepta‐5‐enoyl)glycerophosphocholine. A possible mechanism for the formation of this unique chain‐shortened glycerophospholipid is proposed. Copyright © 2000 John Wiley & Sons, Ltd.

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Pefabloc, 4-[2-aminoethyl]benzenesulfonyl fluoride, is a new, potent nontoxic and irreversible inhibitor of PAF-degrading acetylhydrolase

Cited by 75 publications

References 20 publications

Hepatic regulation of platelet-activating factor acetylhydrolase and lecithin: Cholesterol acyltransferase biliary and plasma output in rats exposed to bacterial lipopolysaccharide

Hepatic regulation of platelet-activating factor acetylhydrolase and lecithin: Cholesterol acyltransferase biliary and plasma output in rats exposed to bacterial lipopolysaccharide

Platelet-Activating Factor Acetylhydrolase Is Mainly Associated With Electronegative Low-Density Lipoprotein Subfraction

Analysis of oxidized glycerophosphocholine lipids using electrospray ionization mass spectrometry and microderivatization techniques

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