Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the effects of a single, oral dose of methotrexate (MTX) on arachidonic acid metabolism in neutrophils from 6 patients with rheumatoid arthritis, which were obtained 1 day before and 1 day after their usual weekly MTX dose. The 6 patients had received a mean weekly MTX dose of 9.6 mg (range 5-15) for a mean of 61.7 months (range 58-64), and none received concomitant corticosteroids. Total generation of leukotriene B4 (LTB4) in neutrophils stimulated ex vivo with 10 microM calcium ionophore A23187 for 20 minutes was significantly suppressed, by a mean of 53%, after the MTX dose compared with the predose levels (mean +/- SEM 13.0 +/- 1.4 ng/10(6) cells versus 6.0 +/- 0.9 ng/10(6) cells; P = 0.0019), reflecting a comparable suppression of both released and cell-retained LTB4. A 49% decrease in omega-oxidation products of LTB4 demonstrates that decreased LTB4 synthesis, rather than increased degradation, is responsible for the decrease in LTB4 generation. The absence of a significant change in either 3H-labeled arachidonic acid release or platelet-activating factor generation indicates that the observed decrease in LTB4 synthesis was apparently not caused by diminished phospholipase A2 activity. A 28% decrease in the total formation of the 5-lipoxygenase products 5-hydroxyeicosatetraenoic acid and the 6-trans-LTB4 diastereoisomers, and a 48% suppression of production of LTB4 plus its omega-oxidation metabolites after the MTX dose suggest inhibition of 5-lipoxygenase activity and possible suppression of leukotriene A4 epoxide hydrolase activity.
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PMID:Inhibition of leukotriene B4 synthesis in neutrophils from patients with rheumatoid arthritis by a single oral dose of methotrexate. 216 85

A sensitive RIA for LTB4 (which cross-reacts 60% with 6-trans LTB4) has been developed with a minimal detectable mass of 7.4 X 10(-15) mole. The properties of a second RIA more specific for 6-trans LTB4 are also described. The latter has utility in the measurement of the enzymatic and non-enzymatic transformations of LTA4 and in the characterisation of inhibitors of LTA4 epoxide hydrolase. Conditions for the direct RIA of immunoreactive LTB4 in human plasma are described. Addition of calcium ionophore, A23187, to human blood increased basal immunoreactive LTB4 levels from less than 100pg ml-1 to 259 +/- 23ng ml-1 (mean +/- SEM, n = 16). Extraction and RPHPLC confirmed that greater than 90% of immunoreactive LTB4 co-eluted with synthetic and [3H]LTB4. Pharmacological characterisation of immunoreactive eicosanoids revealed that in vitro the NSAIDs: aspirin, indomethacin, flurbiprofen and benoxaprofen did not inhibit LTB4 but inhibited TXB2, consistent with cyclo-oxygenase inhibition whereas the prototype mixed inhibitor BW755c inhibited both LTB4 and TXB2. This experimental paradigm may be used in the clinical measurement of the bio-availability of novel agents that inhibit eicosanoid biosynthesis.
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PMID:Radioimmunoassay of LTB4 and 6-trans LTB4: analytical and pharmacological characterisation of immunoreactive LTB4 in ionophore stimulated human blood. 301 87

The glucuronyl transferase activity was measured with 1-naphthol as a substrate in nuclear and microsomal fractions of the human intestinal mucosa. The mucosa was obtained from different parts of the intestine. The rate of 1-naphthol glucuronidation ranged between 0.70 and 1.26 nmol/mg/min (nuclear fraction) and 0.21 and 0.54 nmol/mg/min (microsomal fraction). The average (+/- SEM) of the nuclear/microsomal ratios of the glucuronyl transferase was 2.48 +/- 0.19. The epoxide hydrolase activity towards styrene oxide was measured in the same subcellular fractions; it was undetectable in the nuclear fraction, whereas it was 0.46 +/- 0.04 nmol/mg/min (mean +/- SEM) in the microsomal fraction. The glucuronyl transferase activity was also measured in nuclear and microsomal fractions of the human liver. The activity (mean +/- SEM) was 1.14 +/- 0.21 nmol/mg/min (nuclei) and 5.00 +/- 0.80 (microsomes). The average of the nuclear to microsomal ratios (mean +/- SEM) was 0.32 +/- 0.03.
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PMID:Glucuronidation of 1-naphthol in nuclear and microsomal fractions of the human intestine. 309 May 69

Epoxide formation from drugs, chemicals, food additives and environmental pollutants is catalyzed by cytochrome P-450 dependent monooxygenase(s). Epoxides are converted to glycols or dihydrodiols by epoxide hydrolase (EH). These enzymes are known to be present in the microsomes of different mammalian tissues and in the hepatic nuclei from rats and humans. The balance between the epoxide forming (AHH) and metabolizing (EH) enzyme activities may provide information about the "epoxide exposure" of a tissue. We thus investigated AHH and EH in the nuclear and microsomal fractions from six livers, four kidneys, four lungs, and two adrenals from human fetuses (gestational age between 15 and 24 weeks). Tissues were obtained at legal abortion for sociomedical reasons. AHH activity was measured according to van Cantfort et al (Biochem Biophys Res Commun 79: 505, 1977) using beno (a)pyrene as substrate. EH was measured as described by Jerina et al (Mol Pharmacol 13:342, 1977) using both styrene oxide (SO) and benzo(a)pyrene-4,5-oxide (BPO) as substrate. The nuclear fraction was isolated by a multistep procedure including centrifugation in high density sucrose ( Pacifici et al, unpublished). The hepatic AHH activity (pmole/min/mg; mean +/- SEM) was 11.5 +/- 2.2 in the nuclear fraction and 34.7 +/- 1.7 in the microsomes. In adrenals it was 6.0 (nuclei) and 4.4 (microsomes). The nuclear fraction from kidneys and lungs did not catalyze this reaction at a measurable rate, whereas microsomal AHH activity was 1.3 +/- 0.3 and 5.3 +/- 1.1, respectively, in these tissues.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Epoxide hydrolase and aryl hydrocarbon hydroxylase in human fetal tissues: activities in nuclear and microsomal fractions and in isolated hepatocytes. 667 72

Earlier studies demonstrated that dietary omega-3 polyunsaturated fatty acid (PUFA) supplementation attenuates the chemotactic response of neutrophils and the generation of leukotriene (LT) B4 by neutrophils stimulated with calcium ionophore; however, the mechanisms and relationship of these effects were not examined. Neutrophils and monocytes from eight healthy individuals were examined before and after 3 and 10 wk of dietary supplementation with 20 g SuperEPA daily, which provides 9.4 g eicosapentaenoic acid (EPA) and 5 g docosahexaenoic acid. The maximal neutrophil chemotactic response to LTB4, assessed in Boyden microchambers, decreased by 69% after 3 wk and by 93% after 10 wk from prediet values. The formation of [3H]inositol tris-phosphate (IP3) by [3H]inositol-labeled neutrophils stimulated by LTB4 decreased by 71% after 3 wk (0.033 +/- 0.013% [3H] release, mean +/- SEM) and by 90% after 10 wk (0.011 +/- 0.011%) from predict values (0.114 +/- 0.030%) as quantitated by beta-scintillation counting after resolution on HPLC. LTB4-stimulated neutrophil chemotaxis and IP3 formation correlated significantly (P < 0.0001); each response correlated closely and negatively with the EPA content of the neutrophil phosphatidylinositol (PI) pool (P = 0.0003 and P = 0.0005, respectively). Neither the affinities and densities of the high and low affinity LTB4 receptors on neutrophils nor LTB4-mediated diglyceride formation changed appreciably during the study. Similar results were observed in neutrophils activated with platelet-activating factor (PAF). The summed formation of LTB4 plus LTB5 was selectively inhibited in calcium ionophore-stimulated neutrophils and was also inhibited in zymosan-stimulated neutrophils. The inhibition of the summed formation of LTB4 plus LTB5 in calcium ionophore-stimulated neutrophils and in zymosan-stimulated neutrophils did not correlate significantly with the EPA content of the PI pool. The data indicate that dietary omega-3 PUFA supplementation inhibits the autoamplification of the neutrophil inflammatory response by decreasing LTB4 formation through the inactivation of the LTA epoxide hydrolase and independently by inhibiting LTB4- (and PAF) stimulated chemotaxis by attenuating the formation of IP3 by the PI-selective phospholipase C. This is the initial demonstration that dietary omega-3 PUFA supplementation can suppress signal transduction at the level of the PI-specific phospholipase C in humans.
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PMID:Dietary omega-3 polyunsaturated fatty acids inhibit phosphoinositide formation and chemotaxis in neutrophils. 838 24

The role of juvenile hormone (JH) esterase (JHE) and epoxide hydrolase (EH) in reproduction of the cotton bollworm, Helicoverpa zea, was investigated. Peak emergence of male and female bollworm adults occurred early in the scotophase. Female adults were added to males in a 1:2 ratio, respectively, at the beginning of the first photophase after emergence (d0). The highest oviposition rates for mated females were noted on d 2-4. The in vitro JH III esterase and JH III EH activity was measured in whole body homogenates of virgin and mated females from d0 to d8 post-emergence. Maximal JHE activity for virgin females occurred on d2 (1.09+/-0.14(+/-1 SEM) nmol of JH III degraded/min/mg protein), which was approximately twice that of mated females on the same day. The same results were observed for EH where the activity peaked on d2 at 0.053+/-0.003 as compared to 0.033+/-0.003 nmol of JH III degraded/min/mg protein, respectively. By d4, both JHE and JH EH activities declined significantly in virgin and mated females and were the same through d7. The developmental changes and effects of mating on JH degradation were similar when measured per insect. The highest levels of JHE and JH EH activity/min/mg protein in d2 virgin and mated females was found in ovaries followed by the carcass and then haemolymph; no EH activity was found in haemolymph as expected. For ovary, the JHE and JH EH activity was highest in virgin compared to mated females. The role of both enzymes in the regulation of reproduction is discussed.
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PMID:Role of juvenile hormone esterase and epoxide hydrolase in reproduction of the cotton bollworm, Helicoverpa zea. 1667 98