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)

Septic or inflammatory stimuli suppress drug metabolism by cytochrome P-450 in the liver, presumably at the pretranslational level. We have shown previously that nitric oxide is responsible at least in part for the inhibition by bacterial lipopolysaccharide of phenobarbital-induced CYP2B1/2 activity in vivo. This was attributed to the interaction of nitric oxide with heme in the active-center of cytochrome P450, leading to enzyme inactivation. Here, we report that endogeneous nitric oxide also contributes to LPS-induced suppression of CYP2B1/2 in vivo by down-regulating the expression of CYP2B1/2 protein and mRNA.
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PMID:Evidence for nitric oxide participation in down-regulation of CYP2B1/2 gene expression at the pretranslational level. 906 89

Cytokines are an essential component in those mechanisms that depress renal function in response to inflammatory diseases of the kidney. We have addressed the role of tumor necrosis factor (TNF) in mediating changes in renal function by isolating a nephron segment, the medullary thick ascending limb of Henle's loop (mTAL), and studying the effects of TNF on ion transport via changes in the activity of two epoxygenases, cyclooxygenase (COX) and cytochrome P450 (CYP450) monooxygenase. This nephron segment generates 20-hydroxyeicosatetraenoic acid (20-HETE) as a principal arachidonate metabolite. However, when challenged with lipopolysaccharide (LPS), the mTAL expresses a considerable capacity to metabolize arachidonic acid (AA) via a COX pathway to form PGE2.
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PMID:The renal medullary thick ascending limb as a model for understanding lipid mediators in sepsis. 944 4

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

This report describes a study of the effects of bacterial endotoxin [lipopolysaccharide (LPS)] on cytochrome P450 levels and ethoxyresorufin O-deethylase (EROD) and glutathione S-transferase (GST) activities in liver and two main immune organs of carp: spleen and head kidney. Also studied was the paucity of the carp drug-metabolizing system in an environment subject to pollution by a polycyclic aromatic hydrocarbon, 3-methylcholanthrene (3MC), when fish respond to an immune activation by lipopolysaccharide (LPS). In the presence of bacterial endotoxin the basal cytochrome P450 levels were decreased in liver and spleen. EROD activity was increased in liver and basal GST activity was increased in spleen. When fish were treated concomitantly with 3MC and LPS, a suppression of cytochrome P450 induction in liver and head kidney was observed. EROD activity induced by 3MC was not modified by administration of LPS. GST activity was suppressed by treatment with LPS and inducing agent in liver and head kidney. In the present study it was found that endotoxin can have profound and differential effects on fish basal biotransformation of drugs in the liver and immune organs. Also, the induction of biotransformation enzymes by 3MC was modified when fish responded to an immune stimulation.
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PMID:Modulation of drug-metabolizing systems by bacterial endotoxin in carp liver and immune organs. 975 7

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 corneal epithelium metabolizes arachidonic acid by a cytochrome P450-(CYP) mediated pathway to 12(R)hydroxy-5,8,10,14-eicosatrienoic acid [12(R)-HETE] and 12(R)hydroxy-5,8,14-eicosatrienoic acid [12(R)-HETrE]. Both metabolites possess potent inflammatory properties with 12(R)-HETrE being a powerful angiogenic factor and assume the role of inflammatory mediators in hypoxia- and chemical-induced injury in the cornea, in vivo. We developed an in vitro model of corneal organ culture to characterize the biochemical and molecular events involved in the increased synthesis of these metabolites. These cultured corneas exhibit epithelial cytochrome P450 CYP-dependent 12(R)-HETE and 12(R)-HETrE synthesis as indicated by chiral analysis and by the ability of CYP enzyme inhibitors to repress their synthesis. Hypoxia greatly and selectively stimulated the synthesis of 12(R)-HETE (7-fold over control normoxic conditions) and 12(R)-HETrE. The bacterial endotoxin, lipopolysaccharide, also increased the synthesis of these eicosanoids, substantiating the notion that this activity may function as an inflammatory pathway. These metabolites were detected in the culture medium by gas chromatography/mass spectroscopy (GC/MS) analysis and their levels significantly increased in hypoxia-treated corneas, further indicating their endogenous formation in response to injury. This in vitro model provides an excellent preparation for studying factors regulating the synthesis of these inflammatory eicosanoids and for isolating, identifying and characterizing the CYP protein responsible for their synthesis.
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PMID:Hypoxia stimulates the synthesis of cytochrome P450-derived inflammatory eicosanoids in rabbit corneal epithelium. 986 71

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

Nonparenchymal cells, particularly Kupffer cells, might play an important role in the modulation of xenobiotic metabolism in liver and its pharmacological and toxicological consequences. This intercellular communication via the exchange of soluble factors was investigated in primary rat Kupffer cells and hepatocytes. Freshly isolated rat Kupffer cells were seeded onto cell culture inserts and cocultured with 5 day old serum-free rat hepatocyte monolayer cultures at a ratio of 1:1 for 2 days. Hepatocyte cultures, Kupffer cell cultures or cocultures were treated with 0.1 ng/ml-10 microg/ml lipopolysaccharide (LPS). Within this concentration range, no significant toxicity was observed in either cell type. In LPS-exposed cocultures, tumor necrosis factor alpha (TNFalpha) levels rose up to 5 ng/ml within 5 h; nitric oxide (NO) levels increased up to 70 microM within 48 h of treatment, both in a dose-dependent fashion. The release of negative (albumin) and positive (alpha1-acid-glycoprotein) acute phase proteins from the hepatocytes was strongly down- and up-regulated, respectively. The simultaneous treatment of the cocultures with phenobarbital and LPS (10 ng/ml) or 3-methylcholanthrene and LPS (10 ng/ml) resulted in a strong down-regulation (85%) of the phenobarbital-induced cytochrome P450 (CYP) isoform CYP2B1 in the hepatocytes whereas the 3-methylcholanthrene-induced isoform CYP1A1 was only weakly affected (15%). This specific down-regulation of CYP2B1 was mediated exclusively by TNFalpha, released from the Kupffer cells. It was not linked with NO release from or inducible NO synthase activity in the hepatocytes. The TNFalpha release was not affected by the two xenobiotics. Acetaminophen tested in these cocultures showed no direct interaction with the Kupffer cells. The use of liver cell cocultures is therefore a useful approach to investigate the influence of intercellular communication on xenobiotic metabolism in liver.
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PMID:Kupffer cell-mediated differential down-regulation of cytochrome P450 metabolism in rat hepatocytes. 1009 72

Acute-phase protein synthesis in the liver during inflammation is regulated via cytokines and glucocorticoids. Using quantitative reverse transcription (RT)-PCR analysis and immunoassay, we explored, in the rat, the response of the acute-phase protein, alpha-2 macroglobulin (A2M), after systemic inflammation induced by lipopolysaccharide (LPS) or localized inflammation induced by turpentine oil (TO). The results indicate that synthesis of A2M is higher following TO-induced inflammation than LPS-induced inflammation and is not correlated with interleukin (IL)-6 or glucocorticoid levels. We studied the putative role of heme in this differential A2M expression following localized vs. systemic inflammation; addition of heme during LPS-induced inflammation can boost the expression of A2M, whereas blocking heme synthesis (by succinyl acetone) or enhancing its consumption in parallel biosynthetic pathways (cytochrome P450 induction by phenobarbital) decreases A2M expression. This decrease was abolished by exogenous heme supplementation. Finally, we demonstrate that heme supplementation is also able to increase the A2M response in female rats to a level similar to that in male rats providing a new insight into the puzzling sexual dimorphism observed previously during localized inflammation. We propose that heme should be considered a new regulatory element in controlling liver A2M expression during inflammation.
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PMID:Heme and acute inflammation role in vivo of heme in the hepatic expression of positive acute-phase reactants in rats. 1010 50

The acute phase response (APR) was induced by five separate intravenous (i.v.) injections of Escherichia coli lipopolysaccharide (LPS, 17 microg/kg each time) in rabbits, with intervals of 1 h. This model was used to study the effects of APR on the activities of hepatic microsomal cytochrome P450 (CYP)-dependent enzyme including drug metabolism. Five female rabbits were included in each of four groups, a control group and three LPS-treated groups (group I, II and III). The rabbits of the control, group I, II and III were killed at 1, 1, 3 and 7 days after saline (control only) or the LPS injection, respectively. The APR was confirmed by increases in rectal body temperature, plasma concentrations of interleukin-6 and C-reactive protein (CRP). Pharmacokinetics of antipyrine before death were examined in every group. Antipyrine was administered (5 mg/kg) at 24 h (control and group I), 3 days (group II) and 7 days (group III) after the first LPS injection. Total body clearance (Cl(tot)) of antipyrine tended to decrease in group I. All the livers were excised for measuring CYP-dependent activities. Total CYP content and several CYP-dependent activities (aminopyrine N-demethylation, aniline 4-hydroxylation and caffeine 3-demethylation) decreased in group I. The maximum velocity (Vmax) values of those enzymes, and the amount of CYP1A1/1A2 and CYP2E1 apoproteins appeared to decrease. Michaelis constant (Km) values of those enzymes were not affected by the APR. Rectal body temperature recovered to normal at 3 days after the first LPS injection in group II and III. The concentration of CRP, albumin, total CYP content and the plasma clearance of antipyrine returned to the control levels at 7 days after the first LPS injection. These results suggest that the metabolism of drugs, including CYP-dependent drug metabolizing activity, is suppressed markedly in incipient APR induction in rabbits, and the drug metabolizing capacity is returned to normal at 7 days after APR induction.
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PMID:The suppressive effects of lipopolysaccharide-induced acute phase response on hepatic cytochrome P450-dependent drug metabolism in rabbits. 1037 93


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