Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatic cytochromes P450 are known to be down-regulated by cytokines, lipopolysaccharide, Gram-positive bacteria, and viruses. Little is known, however, about the regulation by inflammation of cytochromes P450 in other tissues. We have found that lipopolysaccharide and interleukin-1 beta stimulate the expression of catalytically active CYP2E1 (but not CYP1A1 or CYP2B) up to 7-fold in rat brain primary cortical glial cultures. The induction reached a maximum after 24 hr and was accompanied by an increase in CYP2E1 mRNA. Chlormethiazole, a specific inhibitor of hepatic CYP2E1 transcription, completely inhibited the induction of CYP2E1 at the mRNA and enzyme levels. Immunofluorescence studies showed CYP2E1 to be expressed in a subset of astrocytes in the lipopolysaccharide-stimulated cortical glial cultures. Using a model of global ischemic injury in the gerbil, we found CYP2E1 to be induced in vivo in astrocytes in the inflammatory phase, 1-3 weeks after the lesion. Likewise, CYP2E1 was induced in the rat cortex 1 week after a focal ischemic injury. Our results suggest tissue-specific regulation of CYP2E1 by inflammatory factors and that CYP2E1 may play a role in astrocytes during inflammation in the brain.
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PMID:Induction of cytochrome P450 2E1 expression in rat and gerbil astrocytes by inflammatory factors and ischemic injury. 891 36

We determined whether dietary ascorbic acid (0.3 or 3 g/kg diet) modulates hepatic microsomal mixed function oxidase (MFO) system and plasma alpha 1 acid glycoprotein (AGP) concentration in chicks treated with Escherichia coli lipopolysaccharide (LPS). Injection of LPS (250 micrograms/kg body weight every other day) intraperitoneally for 14 days decreased cytochromes P450 and b, content and NADPH-cytochrome c reductase activity in hepatic microsomes in male broilers. Content of cytochromes P450 and b5 was negatively correlated with plasma AGP concentration. Feeding ascorbic acid partly alleviated the reduction of cytochromes P450 and b5 in males. Plasma AGP concentration also increased with the LPS injection and was partly lowered by feeding ascorbic acid. The results indicate that dietary ascorbic acid modulates the responses of the microsomal MFO system and of plasma AGP concentration against repeated injection of LPS in male broiler chicks.
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PMID:Effect of dietary ascorbic acid on the hepatic microsomal mixed function oxidase system in liver of chicks treated with Escherichia coli lipopolysaccharide. 946 82

We hypothesized that macrophage activation results in nitric oxide (NO) production and that this NO acts directly on Leydig cells (LC) to alter androgen synthesis. Both peritoneal macrophages and a murine macrophage cell line (RAW 264.7) were activated in vitro by sequential exposure to interferon-gamma (50 U/ml) and then bacterial lipopolysaccharide (LPS; 100 ng/ml) for 24 h each. At various times after initiation of activation, selected wells were harvested for identification of messenger RNA for inducible NO synthase by RT-PCR. Amplicons of the predicted 651-bp product were isolated, cloned, and sequenced to validate the PCR procedure. Such amplicons first appeared between 2-4 h after exposure to LPS, and staining increased in intensity for the rest of the study. Nitrite accumulation followed a similar time course. Similarly treated wells were washed after 24-h activation and cocultured with purified LC for a final 24-h incubation in the absence of interferon-gamma and LPS. Basal and LH-stimulated production of androgen was estimated by RIA. In some experiments the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester or the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (C-PTIO) was added during activation and coculture. Coculture of LC with quiescent macrophages altered neither basal nor LH-stimulated androgen production. Coculture with either type of activated macrophage did not alter basal, but significantly reduced (by 50%) LH-stimulated, androgen production. N(omega)-Nitro-L-arginine methyl ester and C-PTIO blocked the inhibitory effect. The NO donor S-nitroso-N-acetyl penicillamine at concentrations greater than 10(-5) M significantly inhibited LH-stimulated androgen production by purified LC (P < 0.01). The inhibitory effect of S-nitroso-N-acetyl penicillamine was evident when exposure exceeded 4 h. Intermediates of steroidogenesis were added to elucidate the site of NO inhibition. The enzymatic inhibition occurred at least in part at 17alpha-hydroxylase/C(17/20) lyase (P450c17). Enzyme inhibition was reversed by C-PTIO. Northern blot analysis indicated that accumulation of messenger RNA for P450c17 was not significantly altered. Therefore, activation of macrophages results in decreased androgen production by cocultured LC. The inhibition is mediated in part by macrophage-derived NO acting directly on the LC via inhibition of at least one of the P450 steroidogenic enzymes.
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PMID:Nitric oxide is a mediator of the inhibitory effect of activated macrophages on production of androgen by the Leydig cell of the mouse. 949 21

The presence of P450 in a murine macrophage cell line, RAW264.7, was investigated to clarify the biological role and regulation of P450. Microsomes of RAW264.7 cells were isolated and subjected to immunoblotting with anti-rat CYP2A1, 2B1, and 4A2 antibodies. The microsomes gave staining bands with all these antibodies, suggesting the presence of mouse Cyp2a, 2b, and 4a isoforms in RAW264.7. RAW264. 7 cells were treated with typical inducers of P450 (phenobarbital, clofibrate, beta-naphthoflavone and 3-methylcholanthrene). None of these chemicals induced these P450s. Stimulation of RAW264.7 cells with lipopolysaccharide (LPS) and interferon-gamma (INF-gamma) which increase inducible nitric oxide synthase (iNOS) and cytokines in cells decreased Cyp4a protein but not Cyp2a and 2b proteins. To identify P450 isoforms in RAW264.7, we used polymerase chain reaction (PCR) primers for mouse Cyp2a4, 2a12, 2b9/10, 4a10, and 4a12. Total RNA was isolated from these cells and converted to cDNA by reverse transcriptase. PCR was done with these primers and the amplified nucleotides were analyzed by a DNA sequencer. Only Cyp2b9/10 and 4a12 primers gave clear bands, although all primers gave clear bands from liver total RNA. Nucleotide sequences of these products amplified by PCR were identical with Cyp2b9 and 4a12. These findings indicate that Cyp2b9 and 4a12 were present in a macrophage cell line, RAW264.7, and the regulation of P450 by inducers and cytokine differed from that in liver.
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PMID:P450 isoforms in a murine macrophage cell line, RAW264.7, and changes in the levels of P450 isoforms by treatment of cells with lipopolysaccharide and interferon-gamma. 963 May 46

The activation of host defense mechanisms down-regulates microsomal cytochrome P450 in cell culture, humans, and animals. Investigation into various aspects of this effect using in vivo models has yet to define clearly the role that cytokines play in this phenomenon. The mechanism of down-regulation by immunostimulants, such as lipopolysaccharide (LPS), is explored with an in vitro model, utilizing a murine hepatoma (Hepa1) and a murine macrophage (IC-21) cell line. It is hypothesized that down-regulation of P450 activity by immunostimulants involves the activation of immune cells and the subsequent release of cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). The effects of immunostimulation on P450 activity are assessed by ethoxyresorufin O-dealkylase, an assay that measures CYP1A activity in Hepa1 cells. Initial studies demonstrated that LPS added directly to hepatoma cells had no effect on the levels of CYP1A1 activity. In contrast, a significant down-regulation in CYP1A1 activity occurred when hepatoma cells were incubated with monocyte conditioned medium obtained by incubating LPS with IC-21 cells. When pentoxifylline, a TNF-alpha synthesis inhibitor, was co-administered with LPS to macrophages, the down-regulation of CYP1A1 activity was prevented. The direct administration of murine recombinant TNF-alpha to hepatoma cells resulted in a down-regulation of CYP1A1 activity. These results implicated the release of TNF-alpha from macrophages as an important step in the down-regulation of CYP1A1 by LPS.
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PMID:Cytokine-mediated down-regulation of CYP1A1 in Hepa1 cells. 971 97

Injection of rats with bacterial lipopolysaccharide down-regulates P450 (P450) 2C11 (2C11) mRNA to about 20% of its control levels after only 6 hr, and this level is maintained for at least 48 hr. Although we and others have demonstrated that this effect may be at least partially mediated by the cytokines interleukin-1, interleukin-6, and tumor necrosis factor-alpha, as well as by glucocorticoids, the time courses and potencies of 2C11 repression by each single mediator suggested that no cytokine alone is responsible for the entire time course of 2C11 suppression during inflammation. Here, we show that transforming growth factor-beta, hepatocyte growth factor, and interleukin-11 are potent inhibitors of 2C11 expression. In all three cases, 0.1 ng/ml was enough to down-regulate 2C11 mRNA levels to 50% of control. Interleukin-8, a cytokine that is secreted during the acute phase response but does not influence the liver acute phase response, did not affect 2C11 expression. The various mediators have different time courses of 2C11 down-regulation, indicating that the roles of each may be different at different phases of the response.
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PMID:Regulation of hepatic cytochrome P450 2C11 by transforming growth factor-beta, hepatocyte growth factor, and interleukin-11. 976 12

To investigate the effect of central inflammation due to bacterial infection, such as meningitis, on the activities of hepatic cytochromes P450 (CYPs), rats were injected intracerebroventricularly (i.c.v.) with 0.1 microg of bacterial lipopolysaccharide (LPS). The LPS i.c.v. injection significantly decreased the total P450 contents (by 30% of the levels of control rats treated with saline i.c.v.), the contents of CYP1A (48%), 2B (54%), 2C11 (37%) and 3A (40%) and related drug metabolizing activities, 7-ethoxycoumarin O-deethylation (36%), imipramine N-demethylation (41%) and erythromycin N-demethylation (33%) in liver microsomes 24 h after the treatment. In contrast, intraperitoneal (i.p.) injection of LPS at the same dose as i.c.v. (0.1 microg) did not significantly affect the hepatic microsomal contents of total P450 or the content of each individual CYP isozyme and its activity. CYP2D1 protein and the activity of imipramine 2-hydroxylase were not significantly decreased by LPS injection regardless of the route of administration. The inhibitory effects of 0.1 microg i.c.v. LPS on the activities of these CYPs were almost equal to those of 10 microg i.p. LPS, and 0.01 microg of i.c.v. LPS significantly decreased the activity of imipramine N-demethylase only. Therefore, the LPS i.c.v. injection resulted in CYP isozyme-selective inhibition at an ineffective dose when injected i.p.. It is suggested that a central inflammation, such as meningitis, differentially decreases the levels of hepatic CYP isozymes. A possible involvement is discussed of the central nervous system in this down-regulation.
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PMID:Differential alterations in levels of hepatic microsomal cytochrome P450 isozymes following intracerebroventricular injection of bacterial lipopolysaccharide in rats. 976 64

In this study, cytochrome P450 (CYP; EC 1.14.14.1)-dependent activities and P450 isoenzyme patterns were determined in human monocytes and macrophages, which play a major role in antigen processing including small molecular weight compounds which cause contact dermatitis or drug-allergic reactions. Using reverse transcriptase-polymerase chain reaction (RT-PCR) we determined the mRNA expression of eight CYPs (1A1, 1A2, 1B1, 2B6/7, 2E1, 3A3/4, 3A7 and 4B1) in human blood monocytes and macrophage subsets 27E10 and RM3/1. To study the influence of known P450 inducers, monocytes were incubated in vitro with ethanol, dexamethasone, cyclosporin A (CSA), benzanthracene (BA), phenobarbital (PB), lipopolysaccharide (LPS) and 12-O-tetradecanoyl-phorbol-13-acetat (TPA) for 24 hr. Percoll density gradient isolated monocytes as well as the pro-inflammatory macrophage subtype 27E10 expressed 1B1, 2E1 and 2B6/7. On the other hand, in the anti-inflammatory macrophage subtype RM3/1, predominantly 1B1 and to some extent 2B6/7 were found. Treatment with cyclosporin A, phenobarbital, benzanthracene or ethanol resulted in induction of the expression of 3A3/4. CYP1B1 was the predominant isoenzyme in all monocytes and macrophages. In monocytes purified by adherence or induced by benzanthracene, lipopolysaccharide or 12-O-tetradecanoyl-phorbol-13-acetat, 1A1 was also expressed. Northern blot analysis confirmed the presence of CYP1B1 in monocytes and macrophages, a presence which was also demonstrated on the protein level by immunoblot and by immunohistochemical staining of the cells. The expression of several CYPs in monocytes/macrophages suggests that these cells may be important in the metabolism of small molecular weight compounds, which play a role in allergic contact dermatitis and drug reactions. Of particular interest is the remarkably strong expression of the recently identified dioxin inducible CYP1B1, known to be present in a wide range of malignant tumors.
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PMID:Cytochrome P450 1B1: a major P450 isoenzyme in human blood monocytes and macrophage subsets. 980 19

The effect of Escherichia coli lipopolysaccharide (LPS), a classic inducer of the acute-phase response, has been analyzed on both constitutive and oltipraz (a chemoprotective agent)-inducible messenger RNAs (mRNAs) and enzyme activities of major cytochromes P450 (CYPs) and glutathione transferases (rGSTs) in rat liver. At the dose administered (1 mg/kg) and the time studied (6 and 24 hours), endotoxin had no effect on the expression of either CYPs and GSTs with the exception of CYP1A2, which was reduced at both mRNA and activity levels. A strong increase of rGSTA1/2, rGSTM1, rGSTP1, CYP1A2, CYP2B1/2, and CYP2E1 was observed after 3 days of treatment with oltipraz (0.075%, wt/wt). Oltipraz induction of these enzymes (with the exception of CYP2E1) was found to be suppressed at both mRNA, protein, and activity levels during the acute-phase response to endotoxin. Moreover, it is shown that oltipraz induction of CYP1A2 and CYP2B1/2 and its suppression by E. coli LPS occurred at a transcriptional level. These data support the idea that the chemoprotective effect of oltipraz is altered in the course of inflammation and that adaptation in chemoprotective strategies should be considered in certain physiopathologic situations.
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PMID:Endotoxin suppresses the oltipraz-mediated induction of major hepatic glutathione transferases and cytochromes P450 in the rat. 982 31

To investigate the role of nitric oxide (NO) in hepatitis-induced endotoxemia, we injected mice intraperitoneally with 250 mg/kg galactosamine (GalN) and 1 mg/kg lipopolysaccharide (LPS) separately and in combination. NO synthesis increased in a dose-dependent manner with LPS. NO generation at 5 hr after administration of LPS was greater than that at 24 hr. Enhancement of NO generation was demonstrated in mice administered GalN and LPS in combination. A nitrosyl-heme signal in 10,000 g supernatant of liver homogenate, due to cytochrome P450 (P450) combining with NO, NO-P450, was detected at more than ten hr and even more after administration of LPS by electron spin resonance (ESR) measurements at 77 degrees K. The strongest NO-P450 signal and most extreme elevation of aspartate oxoglutarate aminotransferase (AST), alanine oxoglutarate aminotransferase (ALT), and lactate dehydrogenase (LDH) in serum and of lysosomal enzyme activity in plasma were observed in the GalN + LPS group. Their potency was greater than in the 10 mg/kg LPS group, which was even greater than in the LPS 1 mg/kg group. The aniline hydroxylase activity was inversely proportional to NO-P450 signal intensity. It appears that NO might contribute to LPS-induced hepatic damage in GalN-sensitized mice through degeneration and inactivation of liver microsomal enzymes by binding P450 active sites.
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PMID:NO contribution to lipopolysaccharide-induced hepatic damage in galactosamine-sensitized mice. 1007 39


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