Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have suggested the possibility that the non-steroidal antiflammatory drug (NSAID), ibuprofen, may inhibit thromboxane (TX) A2 synthase activity in addition to inhibiting cyclooxygenase activity. Microsomal fractions isolated from the cat lung contain cyclooxygenase as well as prostacyclin (PGI2) synthase, TX synthase, and a GSH-dependent prostaglandin (PG) E2 isomerase activities. When [1-14C] PG endoperoxide H2 (PGH2) was used as substrate, ibuprofen, indomethacin, and meclofenamate exhibited differential effects on terminal enzyme activities. Ibuprofen, at concentrations up to 1 mM, had no effect on the activities of PGI2 synthase, TXA2 synthase of GSH-dependent PGE2 isomerase, whereas indomethacin selectively inhibited PGI2 synthase activity at 5 X 10(-4) M and 10(-3) M. Meclofenamate selectively inhibited TXA2 synthase activity at 5 X 10(-4) M and 10(-3) M. At concentrations of 5 X 10(-3) M, this selectivity was not observed, and indomethacin and meclofenamate decreased the formation of both 6-keto-PGF1 alpha and TXB2. These data indicate that the choice of NSAID and the concentration employed may specifically alter PGH2 metabolism. This action may affect the physiologic consequences of the exchange of PGH2 between cells. The data further indicate that indomethacin has the potential for use as a tool to specifically attenuate PGI2 synthase activity in vitro.
Mol Cell Biochem 1989 May 04
PMID:Differential effects of ibuprofen, indomethacin, and meclofenamate on prostaglandin endoperoxide H2 metabolism. 250 61

The effects of CGS 13080, a thromboxane (TXA2) synthase inhibitor, on airway responses to arachidonic acid (AA) were investigated in the anesthetized cat. Feline and human lung microsomal fraction exhibited prostaglandin I2 (PGI2, prostacyclin), and TXA2 synthase activities, and human platelet microsomal fractions exhibited TXA2 synthase activity. Cat and human lung microsomal fractions, but not human platelets, exhibited the presence of GSH-dependent PGE2 isomerase activity. CGS 13080 inhibited TXA2 synthase activity in all three microsomal fractions in a concentration-dependent manner. The increases in transpulmonary pressure and lung resistance and decreases in dynamic compliance in response to AA were decreased significantly by CGS 13080. These data suggest that the bronchoconstrictor actions of AA are mediated in large part by the formation of TXA2. The data further indicate that cyclooxygenase products other than TXA2 are involved in the bronchoconstrictor response to AA since meclofenamate had greater inhibitory activity than did CGS 13080. Moreover, the effects of CGS 13080 were due to inhibition of TXA2 synthase rather than an effect on TXA2 receptors, since airway responses to the TXA2 mimic, U46619, were not altered. The present data show that CGS 13080 inhibits TXA2 synthase activity without altering cyclooxygenase, PGI2 synthase, or GSH-dependent PGE2 isomerase activities. The data further indicate that in vivo administration of CGS 13080 may selectively increase PGI2 synthase activity.
Mol Cell Biochem 1989 Jan 23
PMID:Inhibition of pulmonary thromboxane A2 synthase activity and airway responses by CGS 13080. 272 78

Glutathione (GSH) transferase isoenzymes have been partially resolved from the cytosol of Schistocephalus solidus (plerocercoid) by GSH affinity chromatography and chromatofocusing at pH 7-5. The presence of isomeric forms was also suggested by analytical isoelectric focusing and high-performance liquid chromatography (HPLC). Gel filtration and sodium dodecyl sulphate-polyacrylamide gel electrophoresis indicated that GSH transferase forms were dimers with a subunit size of approximately 24 kDa. The major GSH transferase form in S. solidus (plerocercoid) showed greater biochemical relationship to the Mu family of mammalian GSH transferase compared to the mammalian Alpha or Pi families. The major subunit purified by GSH affinity chromatography and reversed-phase HPLC also showed high N-terminal homology with the Mu family. A minor GSH transferase form appeared more biochemically related to the Alpha family with respect to substrate specificity and inhibitor sensitivity. The major GSH transferase was inhibited by haematin-related compounds, bile acids and a number of anthelmintics including members of the benzimidazole and phenol-based class of compounds. The major GSH transferase had conjugating activity with members of the trans, trans-2,4-alkadienal and trans-2-alkenal series, secondary products of lipid peroxidation.
Mol Biochem Parasitol 1989 Sep
PMID:Purification of cytosolic glutathione transferases from Schistocephalus solidus (plerocercoid): interaction with anthelmintics and products of lipid peroxidation. 277 Jul 89

Reperfusion of isolated rabbit heart after 60 min of ischaemia resulted in poor recovery of mechanical function, release of reduced (GSH) and oxidized glutathione (GSSG), reduction of tissue GSH/GSSG ratio and shift of cellular thiol redox state toward oxidation, suggesting the occurrence of oxidative stress. Pretreatment of the isolated heart with propionyl-L-carnitine (10(-7) M) improved the functional recovery of the myocardium, reduced GSH and GSSG release and attenuated the accumulation of tissue GSSG. This effect was specific for propionyl-L-carnitine as L-carnitine and propionic acid did not modify myocardial damage.
Mol Cell Biochem
PMID:Protective effect of propionyl-L-carnitine against ischaemia and reperfusion-damage. 277 35

The mechanism of the azo reduction of sulfonazo III and amaranth by the rat hepatic monooxygenase system was studied. Air strongly inhibited (greater than 95%) the enzymatic reduction of both azo compounds; a 100% CO atmosphere inhibited amaranth reduction (greater than 90%) but only slightly inhibited sulfonazo III reduction (13%). The addition of 50 microM sulfonazo III to microsomal incubations stimulated oxygen consumption, NADPH oxidation, and adrenochrome formation, whereas 100 microM amaranth did not. The reduction potentials of these two azo compounds were also very different (amaranth, E = -0.620 V; sulfonazo III, E = -0.265 V versus normal hydrogen electrode). The organic mercurial mersalyl converted cytochrome P-450 to cytochrome P-420 (68%) and markedly decreased NADPH-cytochrome P-450(c) reductase activity (97%) in microsomal preparations, presumably by inactivating or destroying functional sulfhydryl groups important for the catalytic activity of these enzymes. GSH was used to restore, and NADP+ to protect, the activities of the monooxygenase components from the effects of mersalyl. The data indicate that inactivation of NADPH-cytochrome P-450(c) reductase inhibits sulfonazo III and amaranth reduction, whereas inactivation of cytochrome P-450 inhibits only amaranth reduction. Furthermore, the reduction of sulfonazo III by purified microsomal NADPH-cytochrome P-450(c) reductase was significantly faster than the rate of reduction of amaranth. These studies demonstrate that two distinct sites of azo reduction exist in the monooxygenase system and that not all azo compounds are reduced by cytochrome P-450.
Mol Pharmacol 1988 Oct
PMID:Two sites of azo reduction in the monooxygenase system. 284 54

The capacity of reduced glutathione (GSH) to protect lung tissue against ozone-induced pulmonary fibrosis was investigated. Male B6C3F1 mice were exposed to 0, 0.2, 0.5, and 1.0 ppm ozone for 23 hr/day for 14 days. During exposures and/or for a period of 90 days after exposures, subgroups of mice at each exposure level were given drinking water containing 30 mM L-buthionine-S,R-sulfoximine (BSO) to lower in vivo levels of GSH. These BSO treatments reduced blood glutamylcysteine synthetase (GCS) activity (regulatory enzyme for GSH biosynthesis) and lung nonprotein sulfhydryl (NPSH) levels in nonexposed animals by approximately half. In contrast, ozone exposures increased blood GCS activity and lung NPSH levels in a concentration-dependent manner, with smaller increases in the BSO-treated mice. Immediately after exposures, an ozone-related inflammatory response was seen in lungs, but no histopathological signs of developing fibrosis were evident. Ninety days later, mice exposed to 1 ppm ozone and not treated with BSO had modest evidence of pulmonary fibrosis. Mice exposed to 1 ppm ozone and treated with BSO during this post-exposure period (regardless of BSO treatment during exposures) showed histopathological evidence of exacerbated pulmonary fibrosis, compared to similarly exposed mice not treated with BSO postexposure. These results indicated that interference with the body's normal defense mechanisms against oxidant damage, including suppression of GSH biosynthesis, exacerbates the subsequent development of pulmonary fibrosis.
Exp Mol Pathol 1988 Oct
PMID:Effects of buthionine sulfoximine on the development of ozone-induced pulmonary fibrosis. 290 82

The more A + T rich fractionated component (FII DNA) of the Halobacterium halobium genome constitutes one third of the total DNA and upon isolation consists of covalently closed circular DNA (pHH1 and minor cccDNA) and nonsupercoiled sequences. We have investigated the physical organization of the non cccDNA in FII by a chromosome walk using one copy of the halobacterial insertion element ISH1 as a start point. This chromosome walk led to the isolation of 160 kb of chromosomal DNA containing 70 kb of FII DNA covalently linked to more G + C rich sequences (FI DNA). Copies of three previously characterized insertion elements (ISH1, ISH2, and ISH26) as well as at least 10 other repeated sequences are clustered within this chromosomal FII DNA "island". Unique sequences are found in the FI DNA flanking the FII DNA island as well as in 40 kb of FI DNA surrounding the bacterio-opsin gene. The presence of pHH1 in H. halobium and closely related species correlates with the occurrence of the characterized chromosomal FII DNA island. Halophilic purple membrane producing isolates YC81819-9, GN101, SB3 and GRA lack pHH1 and the 70 kb FII DNA, but contain all of the FI DNA sequences tested. We propose that pHH1 and this chromosomal FII DNA are characteristic genomic components of H. halobium and closely related species, and, that the 70 kb FII DNA might represent a large insertion in the chromosome of H. halobium and closely related species. The conservation of both FI and FII DNA sequences can be used for strain classification and determination of evolutionary relationships among halo-bacteria.
Mol Gen Genet 1985
PMID:Genome organization in Halobacterium halobium: a 70 kb island of more (AT) rich DNA in the chromosome. 298 57

The possibility that glutathione (GSH) S-transferases may affect microsome-mediated methylation of DNA by dimethylnitrosamine (DMN) in vitro has been investigated using aflatoxin B1 (AFB1) as a positive control. Hamster liver microsomes were incubated with either [14C]DMN or [3H]AFB1 and calf thymus DNA, with or without GSH and hamster cytosol. Although a significant amount of DMN was metabolized, GSH alone or in conjunction with cytosol or purified GSH S-transferases did not affect the binding of 14C to DNA and the amount of 7-methylguanine formed. However with AFB1, a significant reduction in both its binding to DNA and in the formation of AFB1-N7Gua adduct with a concomitant increase in AFB1-GSH conjugation was observed, suggesting that the test system was functioning effectively.
Mol Toxicol
PMID:Lack of effect of glutathione on the binding of dimethylnitrosamine to DNA in vitro. 313 May 67

2-Bromo-(diglutathion-S-yl)hydroquinone [2-Br-(diGSyl)HQ] causes severe necrosis of the proximal renal tubules in the rat, elevations in blood urea nitrogen (BUN) and increased urinary excretion of protein, glucose, and lactate dehydrogenase. In contrast, 2-Br-3-(GSyl)HQ, 2-Br-5-(GSyl)HQ, and 2-Br-6-(GSyl)HQ caused differentially less toxicity than the diglutathionyl conjugate. None of these conjugates had any apparent effect on liver pathology and serum glutamate-pyruvate transaminase remained within the normal range. Pretreatment of rats with probenecid, an organic anion transport inhibitor, offered only slight protection against 2-Br-(diGSyl)HQ-mediated elevations in BUN, proteinuria, or glucosuria. In contrast, quinine, an organic cation transport inhibitor, potentiated the nephrotoxicity of 2-Br-(di-GSyl)HQ. Thus, in contrast to other nephrotoxic sulfur conjugates, probenecid-sensitive organic ion transport systems do not contribute to the kidney-specific toxicity of 2-Br-(diGSyl)HQ. However, inhibition of renal gamma-glutamyl transpeptidase by AT-125 completely protected rats from the nephrotoxic effects of 2-Br-(diGSyl)HQ. Aminooxyacetic acid, an inhibitor of cysteine conjugate beta-lyase, caused a 20-25% decrease in 2-Br-(diGSyl)HQ-mediated elevations in BUN and urinary excretion parameters. The isomeric 35S conjugates covalently bound to rat kidney 10,000 x g homogenate in the order 2-Br-6-(GSyl)HQ greater than 2-Br-5-(GSyl)HQ greater than 2-Br-3-(GSyl)HQ greater than 2-Br-(diGSyl)HQ. AT-125 (0.4 mM) decreased covalent binding by 25%, 17%, 33%, and 28%, respectively. Aminooxyacetic acid (0.1 mM) inhibited covalent binding by 26%, 10%, 17%, and 17% respectively. Ascorbic acid (1.0 mM) inhibited covalent binding by 63%, 87%, 62%, and 28%, respectively, and this inhibition correlated, inversely, with the redox potential of the conjugates. Thus, the covalent binding is mediated preferentially by oxidation of the quinol moiety, although the formation of reactive thiols cannot be excluded. In addition, the initial conjugation of 2-BrHQ with GSH does not result in the formation of a less redox-active species. However, the subsequent addition of a second molecule of GSH results in the formation of a more redox-stable compound, which, paradoxically, enhances toxicity. The metabolism of 2-Br-(diGSyl)HQ by renal proximal tubular gamma-glutamyl transpeptidase and trans-membrane transport of the cysteine conjugate(s) followed by oxidation of the quinol moiety is probably responsible for the target organ toxicity of this compound.
Mol Pharmacol 1988 Oct
PMID:2-Bromo-(diglutathion-S-yl)hydroquinone nephrotoxicity: physiological, biochemical, and electrochemical determinants. 317 33

N-acetyl-p-benzoquinone imine (NAPQI), a reactive metabolite of acetaminophen, has previously been shown to be toxic to hepatocytes freshly isolated from rat liver [Mol. Pharmacol. 28:306-311 (1985)] NAPQI arylates and oxidizes cellular thiols, and either one or both reactions may be important in the pathogenesis of cytotoxicity. Two dimethylated analogues of NAPQI, N-acetyl-3,5-dimethyl-p-benzoquinone imine (3,5-diMeNAPQI) and N-acetyl-2,6-dimethyl-p-benzoquinone imine (2,6-diMeNAPQI), were prepared to determine whether one reaction might be more damaging to cells than the other. Of the three quinone imines, the least potent cytotoxin to rat hepatocytes was 3,5-diMeNAPQI. However, the cytotoxicity of 3,5-diMeNAPQI was markedly enhanced by pretreatment of cells with 1,3-bis-(2-chloroethyl)-N-nitrosourea, which inhibits glutathione reductase. Reactions of 3,5-diMeNAPQI with GSH, both chemically and in hepatocytes, indicated that this quinone imine primarily oxidized thiols. These findings were corroborated by results of covalent binding experiments, which showed that radiolabeled 3,5-diMeNAPQI bound only to a small extent to hepatocyte proteins. On the other hand, 2,6-diMeNAPQI, the most potent cytotoxin of the three quinone imines that was investigated bound extensively to hepatocyte proteins. In addition, 2,6-diMeNAPQI reacted with GSH, both chemically and in hepatocytes, to form significant amounts of GSSG. Reduction products of NAPQI and its dimethylated analogues were not important contributors to cytotoxicity or GSSG formation based on the following results: 1) the quinone imines did not increase oxygen consumption by hepatocytes nor did they lead to oxygen uptake in solution; 2) dicoumarol, an inhibitor of the reductase, DT-diaphorase, had no effect on cytotoxicity caused by the quinone imines. Evidence for the involvement of ipso-adducts of the quinone imines in their reactions with cellular thiols is provided by results of investigations on the effects of DTT on the metabolism, covalent protein binding, and cytotoxic effects of the quinone imines.
Mol Pharmacol 1988 Oct
PMID:Comparative cytotoxic effects of N-acetyl-p-benzoquinone imine and two dimethylated analogues. 317 35


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