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

Bacterial lipopolysaccharide (LPS) and a diverse array of other immunostimulants and cytokines suppress the metabolism of endogenous and exogenous substances by reducing activity of the hepatic cytochrome P450 mixed-function oxidase system. Although this effect of immunostimulants was first described almost 40 yr ago, the mechanism is obscure. Immunostimulants are now known to cause NO overproduction by cells via induction of nitric oxide synthase. We have investigated whether NO overproduction is involved in suppressing hepatic metabolism by LPS. In vitro treatment of hepatic microsomes with NO, produced by chemical decomposition of 3-morpholinosydnonimine or by nitric oxide synthase, substantially suppressed cytochrome P450-dependent oxygenation reactions. This effect of NO was seen with hepatic microsomes prepared from two species (rat and chicken) and after exposure to chemicals that induce distinct molecular isoforms of cytochromes P450 (beta-naphthoflavone, 3-methylcholanthrene, and phenobarbital). Spectral studies indicate that NO reacts in vitro with both Fe(2+)- and Fe(3+)-hemes in microsomal cytochromes P450. In vivo, LPS diminished the phenobarbital-induced dealkylation of 7-pentoxyresorufin by rat liver microsomes and reduced the apparent P450 content as measured by CO binding. These LPS effects were associated with induction of NO synthesis; LPS-induced NO synthesis showed a strong positive correlation with the severity of cytochrome P450 inhibition. The decrease in both hepatic microsomal P450 activity and CO binding caused by LPS was largely prevented by the selective NO synthase inhibitor N omega-nitro-L-arginine methyl ester. Our findings implicate NO over-production as a major factor mediating the suppression of hepatic metabolism by immunostimulants such as LPS.
 ...
PMID:Nitric oxide is a mediator of the decrease in cytochrome P450-dependent metabolism caused by immunostimulants. 750 96

Interleukin-2 (15 micrograms/mouse, i.p. twice daily for 4 days and once on the 5th day) significantly lowered cytochrome P-450 and heme content and increased heme oxygenase mRNA accumulation; the activities of 7-ethoxycoumarin O-deethylase, ethoxy- and pentoxyphenoxazone O-dealkylases were decreased. The activity of the type O form of hepatic xanthine oxidase increased, but there was no increase in lipid peroxide, expressed in terms of microsomal malondialdehyde. In vivo inactivation of xanthine oxidase activity by feeding mice with tungstate did not substantially change the degree of interleukin-2-induced cytochrome P-450 depression, suggesting that the two processes are not causally linked. Induction of tolerance to endotoxin by a 4-day pretreatment with lipopolysaccharide resulted in 50% protection against this depression despite inhibition of the interleukin-2 induced formation of tumor necrosis factor. This suggests that the release of tumor necrosis factor per se does not fully account for the depression of cytochrome P-450. Dexamethasone, already used in patients to reduce the toxicity of interleukin-2 therapy, provided full protection against the cytochrome P-450 depression.
 ...
PMID:Mechanisms of interleukin-2-induced depression of hepatic cytochrome P-450 in mice. 779 64

We investigated regulation of macrophage prostaglandin production during activation by interferon gamma (IFN-gamma) and lipopolysaccharide (LPS). An in vitro model was established using the mouse macrophage-like cell line RAW 264.7. Cells were cultivated in the presence of IFN-gamma and LPS for up to 48 h and changes in the secretion of nitric oxide (NO.) and tumor necrosis factor alpha (TNF-alpha) were observed as activation markers. Under these conditions a prompt and strong increase in PGE2 production was found in the first 8 h followed by nearly constant generation of PGE2 during the next 40 h. In contrast, the activity of prostaglandin endoperoxide synthase (PGHS), measured as PGE2 production of microsomal protein fractions, was also increased, but reached a clear maximum at 24 h. Recently a second form of PGHS was cloned (PGHS-2) and specific antibodies and mRNA probes for both isoforms are available. PGHS-2 enzyme was expressed maximally after 24 h of activation whereas PGHS-1 was not influenced. In the presence of IFN-gamma and LPS, PGHS-2 mRNA expression reached a maximum at 8 h but PGHS-1 mRNA was not induced during the whole time period. These data indicate that changes in PG synthesis following macrophage activation are due to regulation of PGHS-2 expression.
 ...
PMID:Transient expression of prostaglandin endoperoxide synthase-2 during mouse macrophage activation. 814 18

The dose-dependent effects of 2,2',3,3',4,4',5,5',6-nonachlorobiphenyl (nonaCB), 2,2',3,3',4,4',5,6,6'-nonaCB, 2,2',3,3',4,5,5',6,6'-nonaCB and decaCB on the suppression of the splenic plaque-forming cell (PFC) response to the T-cell-dependent antigen, sheep red blood cells (SRBCs) and the T-cell-independent antigen, trinitrophenyl-lipopolysaccharide (TNP-LPS), were determined in genetically inbred mice. In addition, the induction of hepatic microsomal ethoxyresorufin O-deethylase (EROD) activity was also measured. The highly chlorinated biphenyls suppressed the splenic PFC response to SRBCs in C57BL/6 and DBA/2 mice and were relatively more active in the former strain. The C57BL/6 mice are more responsive to aryl hydrocarbon (Ah) receptor agonists than DBA/2 mice and these data support a possible role for the Ah receptor in mediating this response. However, previous studies with polychlorinated biphenyls (PCBs) indicate that congeners with 3 or 4 ortho-chloro substituents are inactive as Ah receptor agonists and this was consistent with the minimal induction of hepatic microsomal EROD activity by the highly chlorinated biphenyls in both strains of mice. Thus, the results suggest that the inhibition of the splenic PFC response to SRBCs observed in this study was primarily an Ah receptor-independent response. Some of the highly chlorinated diphyenyl ethers namely decachlorodiphenyl ether and 2,2',3,3',4,4',5,6,6'-nonachlorodiphenyl ether, inhibited the antigenic response to TNP-LPS in C57 BL/6 mice. The results indicate that the suppression of the TNP-LPS-mediated immune response may be a more reliable indicator of the Ah receptor-dependent immunotoxicity of halogenated hydrocarbons.
 ...
PMID:Immunosuppressive effects of highly chlorinated biphenyls and diphenyl ethers on T-cell dependent and independent antigens in mice. 830 8

Previous studies from our laboratory suggested that phorbol 12-myristate 13-acetate (TPA) stimulates prostaglandin E2 (PGE2) production by inducing de novo synthesis of prostaglandin H synthase (PHS) in a rat tracheal cell line. We report here an extension of this work to further elucidate the mechanisms by which TPA (and epidermal growth factor) stimulates PGE2 production. We used the rat tracheal cell line EGV6, which has a lower basal level of PGE2 production and responds to TPA and EGF stimulation with a much greater increase in PGE2 synthesis than the previously used cell line, Incubation of EGV6 cultures with TPA or EGF resulted in a time- and dose-dependent increase in PGE2 synthesis up to 40-fold and 6-fold, respectively. Serum also stimulated PGE2 synthesis, while bombesin, retinoic acid, and bacterial lipopolysaccharide did not. PHS protein levels in microsomal preparations from the cells were estimated by Western analysis. Antibodies raised against murine PHS-2 cross reacted with the EGV-6 PHS while several antibody preparations that react with PHS-1 from ram or mouse reacted poorly with the cellular preparation. TPA treatment increased the de novo synthesis of PHS-2 while dexamethasone treatment reduced the response to TPA. Northern blot analysis of mRNA from EGV6 cultures using a ram PHS cDNA revealed a 2.8- and a 4.5- to 4.9-kb (designated 4.9 kb) transcript. Treatment with TPA or EGF increased the expression of both transcripts and this effect was further enhanced by cyclohexamide. To further define the PHS mRNA species of EGV6 cells, two well-characterized murine PHS cDNA probes were used. The constitutive murine PHS cDNA probe hybridized only with the 2.8-kb transcript, and the inducible murine PHS cDNA hybridized only with the 4.9-kb transcript. The rates of induction as well as degradation of the 4.9-kb PHS mRNA were much more rapid than those of the 2.8-kb mRNA species. Dexamethasone partially inhibited the induction of both PHS transcripts by TPA. Southern analysis of genomic EGV6 DNA indicated the presence of two distinct PHS genes in these cells. Taken together these findings indicate that two PHS genes are expressed in rat tracheal epithelial cells. In contrast to the PHS genes expressed in murine (and chicken) fibroblasts in which only the gene coding for the larger mRNA species is transcriptionally regulated, in the rat tracheal cells both genes are positively regulated by TPA and EGF and downregulated by glucocorticoids.
 ...
PMID:Phorbol ester and epidermal growth factor enhance the expression of two inducible prostaglandin H synthase genes in rat tracheal epithelial cells. 832 87

The dose-dependent effects of a single acute exposure of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), 1,2,3,7,9-PeCDF, 1,3,6,8-tetrachlorodibenzofuran (TCDF), 3,3',4,4',5-pentachlorobiphenyl (pentaCB), and 3,3,',4,4',5,5'-hexaCB on the suppression of the splenic plaque-forming cell (PFC) response to the T-cell-independent antigen trinitrophenyl-lipopolysaccharide were determined in C57BL/6 and DBA/2 mice. In addition, the induction of hepatic microsomal ethoxyresorufin O-deethylase (EROD) activity was also measured in these animals. 2,3,7,8-TCDD and 2,3,4,7,8-PeCDF were the most immunotoxic congeners in both strains of mice and with the exception of the latter congener, the ED50 values for each compound were lower in the C57BL/6 than the DBA/2 mice. 2,3,7,8-TCDD induced hepatic microsomal EROD activity in both strains of mice whereas the other congeners were considerably less active or inactive as inducers. The results of this study demonstrated that for the halogenated aromatic hydrocarbons the immunotoxic response was a more sensitive indicator of exposure than the induction of CYP1A1 activity. The rank order for the immunotoxic potencies of the chlorinated aromatic compounds used in this study was 2,3,7,8-TCDD approximately 2,3,4,7,8-PeCDF > 3,3',4,4',5-pentaCB approximately 3,3',4,4',5,5'-hexaCB > 1,2,3,7,9-PeCDF > 1,3,6,8-TCDF. The order of activity for these congeners was similar for other Ah receptor-mediated responses and these results coupled with the differential responsiveness of the C57BL/6 and DBA/2 mice confirms the role of aryl hydrocarbon (Ah) receptor in mediating the suppression of this T-cell-independent response.
 ...
PMID:Immunotoxic potencies of polychlorinated biphenyl (PCB), dibenzofuran (PCDF) and dibenzo-p-dioxin (PCDD) congeners in C57BL/6 and DBA/2 mice. 832 2

A novel fluorescence assay for phospholipase A2 [Wilton (1990) Biochem. J. 266, 435-439] has been used to study the Group-II rat liver mitochondrial enzyme, and a number of novel properties of this enzyme were identified. (1) The enzyme activity was located in the liver macrophages (Kupffer cells) while negligible activity was associated with hepatocytes. (2) Although subcellular fractionation of whole liver confirmed the predominantly mitochondrial location of this enzyme activity, the analysis of the hepatocyte-free Kupffer-cell-enriched fraction revealed a different enzyme distribution, with the majority of activity being associated with the microsomal membrane fraction. (3) Bacterial endotoxin has been previously shown to be scavenged by Kupffer cells in rats. Treatment of rats with bacterial lipopolysaccharide (endotoxin) resulted in a dramatic time- and dose-dependent increase in liver phospholipase A2 activity. (4) It is known that injection of endotoxin into rodents results in elevated serum phospholipase A2 activity, while a similar phenomenon is seen in the condition of septic shock in man. The source of this serum enzyme was unknown. In this study perfusion of livers from rats pretreated with lipopolysaccharide with physiological saline demonstrated a 6-fold increase in phospholipase A2 activity in the perfusate compared with sham-treated controls, with only minor release of hepatic lipase. (5) Western-blot analysis confirmed an increased release of this Group-II phospholipase A2 into the perfusate of lipopolysaccharide-treated rats compared with sham-treated controls. These results suggest that liver Kupffer cells are a major source of the endotoxin-induced serum Group-II phospholipase A2 activity associated with bacterial infection and trauma.
 ...
PMID:Rat liver mitochondrial phospholipase A2 is an endotoxin-stimulated membrane-associated enzyme of Kupffer cells which is released during liver perfusion. 832 56

The experiments carried out on mongrel male mice showed that bacterial lipopolysaccharide Prodigiozan inhibit the activity of P-450-dependent monooxygenases of the liver, thus changing the activity of antidepressants--amitriptyline and imipraminum. The data on biological activity were tested in "tail suspension" test. Prodigiozan exhibited no central effect. Changes in biotransformation processes after single administration of both drugs resulted in the delay and prolongation of the effect. Prodigiozan prevents the induction of microsomal enzymes caused by antidepressants. Amitriptyline do not affect the immunostimulating action of prodigiozan, whereas imipraminum inhibited prodigiozan activity.
 ...
PMID:[Prodigiozan modulation of the specific activity of antidepressants]. 870

The fungal metabolite trichodimerol (BMS-182123) has demonstrated inhibition of lipopolysaccharide (LPS)-stimulated tumor necrosis factor-alpha (TNF-alpha) secretion in various in vitro macrophage models (human and murine) including primary and tumor cell lines. When challenged with LPS, differentiated THP-1 monocytic cells secrete elevated levels of the cyclooxygenase products prostaglandin E2 (PGE2), thromboxane B2, and prostaglandin F2alpha (PGF2alpha). Studies directed at elucidating the mechanism of action of BMS-182123 as a TNF-alpha inhibitor revealed that the compound has a profound inhibitory effect on prostanoid secretion in response to LPS challenge. The key enzymes in prostaglandin synthesis are the constitutive cyclooxygenase, prostaglandin H synthase-1 (PGHS-1), and the mitogen-induced cyclooxygenase (PGHS-2), which is induced upon LPS stimulation in THP-1 cells. BMS-182123 did not inhibit the cyclooxygenase activity of PGHS-1 in an in vitro assay, suggesting that inhibition is due to a blockade in synthesis of cyclooxygenase enzyme. Western blot analysis of microsomal pellets from THP-1 cells stimulated with LPS (with or without BMS-182123 pretreatment) provided convincing evidence that the inhibition of prostaglandin synthesis is a result of suppressed synthesis of PGHS-2 enzyme. Northern blot analysis of THP-1 RNA demonstrated that BMS-182123 inhibits the induction of PGHS-2 at the level of transcription.
 ...
PMID:Trichodimerol (BMS-182123) inhibits lipopolysaccharide-induced eicosanoid secretion in THP-1 human monocytic cells. 877 89

Bacterial lipopolysaccharide (LPS) has been previously shown to down-regulate the mRNA and protein expression of the hepatic cytochrome P450 (P450) isozymes 2C11 and 2C12. In this study, we examined the effects of LPS on the constitutive expression of P4503A2, P4502E1, and the P4504A subfamily in the rat. Fischer 344 and Sprague-Dawley rats were each administered 1 mg/kg LPS intraperitoneally and killed for hepatic RNA and microsome isolation at different times. LPS treatment was found to suppress P4502C11, P4503A2, and P4502E1 protein and mRNA expression in both strains of rat. Total microsomal P450 levels decreased by 30%, which was smaller than the effects on the levels of individual isozymes. The magnitude of suppression exhibited in the Sprague-Dawley rats, however, seemed to be more variable than that in the F344 strain. The mRNAs of all three of the P4504A subfamily members were induced 2- to 6-fold in the F344 rat livers after LPS administration. P4504A3 protein expression increased 2-fold, whereas P4504A1/2 protein levels decreased by 30%. Lauric acid omega-hydroxylase activity increased 1.6-fold in LPS-treated Fischer 344 rats and omega-1-hydroxylase activity decreased by 38%. In the Sprague-Dawley strain, however, decreases were seen in both omega- and omega-1-hydroxylase activities after LPS treatment. Our data demonstrate that LPS administration induces P4504A subfamily mRNA and P4504A3 protein expression. Furthermore, our findings also suggest strain differences in both suppression and induction of P450s between the Sprague-Dawley and F344 rats.
 ...
PMID:Endotoxemia in rats is associated with induction of the P4504A subfamily and suppression of several other forms of cytochrome P450. 880 Oct 54


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>