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)

The effect of a single dose of bacterial endotoxin (lipopolysaccharide, LPS) was compared with that of tumor implantation in mice on the activity of several hepatic cytochrome P-450-dependent monooxygenases. These included ethoxycoumarin O-deethylase, p-nitrophenol hydroxylase, aminopyrine N-demethylase, pentoxyresorufin O-depentylase, ethoxyresorufin O-deethylase and testosterone hydroxylase. For this purpose, mice were treated i.p. with 5 micrograms of LPS or implanted in the right paw with S 180 sarcoma. A comparable depression (30-50%) of total microsomal P-450 content as well as of the different P-450 monooxygenase activities tested was observed in LPS-treated mice (24 h after LPS) and in tumor bearing mice (12 days after implantation). The lack of differences in the pattern of depression of microsomal enzymes between LPS-treated and tumor-bearing mice suggests that a common mechanisms might be involved in the depression of P-450 by LPS or S-180 implantation.
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PMID:Depression of hepatic drug metabolism in endotoxin-treated and sarcoma-bearing mice. 160 46

Intravenous treatment of male rats with recombinant human interleukin-6 (rhIL6) at 50, 100 and 200 micrograms/kg (corresponding to 4, 8 and 16 x 10(4) U/animal, respectively) reduced the activities of hepatic microsomal cytochrome P450-dependent monoxygenases to varying degrees. Ethylmorphine-N-demethylase activity fell to 53% of control values, an effect similar to that induced by 2.5 mg/kg Escherichia coli lipopolysaccharide (LPS). Ethoxycoumarin-O-deethylase activity was also sensitive to inhibition, whereas IL6 had little effect on the activities of other P450-dependent enzymes, including ethoxyresorufin-O-deethylase. Pentoxyresorufin dealkylase activity, which is representative of the cytochrome P450 IIB 1/2 subfamily, was unaffected by IL6 whereas LPS reduced it to 33.7% of control values. Another hepatocyte-related parameter, serum concentration of alpha 1-acid glycoprotein (AGP), was increased by up to 3.5-fold over baseline by IL6 and 10-fold by LPS. Recombinant human interleukin-1 beta (rhIL1 beta) (10 micrograms/kg, corresponding to 5 x 10(4) U/rat) and recombinant human tumor necrosis factor alpha (rhTNF) (150 micrograms/kg corresponding to 24 x 10(4) U/rat) were both as potent as LPS (2.5 mg/kg) in increasing serum AGP levels and reducing hepatic microsomal monoxygenase activities. IL6 did not potentiate the effects of rhIL1 beta. Hepatic microsomal glucuronyltransferase activities were little affected by LPS and unaffected by rhIL6. Finally, rhIL6 was more potent after i.p. injection than after i.v. or s.c. injection. These results suggest that the effects of LPS, TNF and IL1 on the mixed-function oxidase system in vivo may be due partly to an induction of IL6 in vivo. The different sensitivities of the enzymes to IL6 but not to IL1 or TNF may be due to the involvement of two distinct mechanisms.
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PMID:Effects of interleukin-6 on cytochrome P450-dependent mixed-function oxidases in the rat. 163 28

Endotoxin depresses cytochrome P450 levels when injected into animals. The purpose of this study was to determine whether endotoxin itself, or monokine(s) released in response to endotoxin administration are responsible for this effect. Cytochrome P450 levels and drug metabolizing activities were measured in endotoxin resistant C3H/HeJ mice 24h after single intraperitoneal injections of either lipopolysaccharide (LPS), a semipurified murine monokine preparation containing interleukin-1 (IL-1), or murine recombinant IL-1. In endotoxin sensitive C3H/HeN mice, LPS (0.5 mg/Kg) decreased total cytochrome P450 levels, benzphetamine demethylase activities, and ethoxyresorufin-0-deethylase activities. This dose of LPS did not alter cytochrome P450 levels or activities in the C3H/HeJ mice. However, after injection of the semipurified monokine preparation or the recombinant IL-1, there were significant decreases in cytochrome P450 levels and activities similar to the decreases observed with LPS in the C3H/HeN mice. These findings suggest that the alterations in hepatic cytochrome P450 seen with endotoxin injection are mediated, at least in part, by IL-1.
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PMID:Interleukin-1 (IL-1) depresses cytochrome P450 levels and activities in mice. 329 45

The possible role for adrenergic influences or prostaglandins in the effects of endotoxin to inhibit the glucocorticoid induction of hepatic tryptophan oxygenase (TO) activity, to decrease the hepatic microsomal cytochrome P--450-dependent drug-metabolizing activity, and to induce heme oxygenase activity was examined. Administration of the alpha-adrenergic locking agents phenoxybenzamine or phentolamine attenuated the inhibitory effect of the bacterial lipopolysaccharide on the induction of TO activity by dexamethasone. Injection of a beta-adrenergic blocker, propranolol, or of indomethacin, an inhibitor of prostaglandin biosynthesis, accentuated the effect of endotoxin to inhibit TO induction. Neither phenoxybenzamine, propranolol, nor indomethacin altered the effect of endotoxin to decrease aniline hydroxylase activity, ethylmorphine N-demethylase activity, or the levels of cytochrome P--450. Also, dexamethasone administration did not significantly protect against the effects of endotoxin on the hepatic microsomal drug metabolizing enzyme system, and none of the pharmacological agents diminished the effects of endotoxin to induce hepatic heme oxygenase activity. Endotoxin administration was also shown to diminish, but not prevent, the induction of cytochrome P--450 and ethylmorphine N-demethylase activity produced by phenobarbital. The results indicate that alpha-adrenergic mechanisms are involved in the endotoxic inhibition of the glucocorticoid induction of TO activity and suggest that neither adrenergic influences nor prostaglandins play a significant role in the effect of endotoxin to decrease hepatic mixed-function oxidase activity.
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PMID:Investigation of adrenergic and prostaglandin influences in the endotoxin alteration of hepatic heme oxygenase, microsomal mixed-function oxidase, and glucocorticoid-induced tryptophan oxygenase activities. 613 93

The frequency of gram-negative infections and endotoxemia in the perinatal period prompted an investigation of the effects of endotoxin (Escherichia coli 026B6) on hepatic drug metabolism. Gravid female rats given injections IP with different dosages of lipopolysaccharide during late pregnancy resulted in significant depression of the liver microsomal cytochrome P-450 dependent monooxygenase activities. The acute administration of endotoxin to mothers (1.4 mg/kg on seventh day after parturition) significantly decreased the hepatic activity of aminopyrine demethylase and contents of cytochrome P-450 of suckling neonates and mothers. However, chronic administration of endotoxin (0.2 mg/kg/day for 7 days) to lactating mothers did not alter neonatal enzyme activities. When neonates themselves were given injections of endotoxin (1.0 mg/kg) at 7, 16, and 27 days of age, a significant reduction in levels of mixed function oxidase enzymes was observed. These observations suggest that the ability of mothers and neonates to metabolize drugs is significantly decreased upon exposure to endotoxin, and this demands careful evaluation of drug disposition studies in gram-negative sepsis.
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PMID:Gram-negative endotoxin administration decreases hepatic drug-metabolizing enzymes during development in rats. 699 41

1. Bacterial endotoxin, a soluble lipopolysaccharide, has been studied to ascertain its effects in vivo and in vitro on the hepatic drug-metabolizing enzymes of adult male and female rats. 2. 24 h after a single 1 X 0 or 2 X 0 mg/kg i.p. dose of endotoxin, hexobarbital sleeping time was significantly increased in adult male rats. Significant inhibition of liver microsomal cytochrome P-450 occurred after 6 h and continued only until 24 h after endotoxin administration, while injection of inactivated endotoxin did not result in any significant decrease of hepatic mixed-function oxidase enzymes or cytochrome P-450. In contrast, rho-nitrophenol-UDP-glucuronyltransferase enzyme activity was unaffected by these levels of endotoxin. 3. Electron-microscopic examination of rat liver hepatocytes did not reveal any significant change in ultrastructure 24 h after a single i.p. dose of endotoxin. 4. Endotoxin failed to depress the phenobarbitone- or 3-methylcholanthrene-induced forms of cytochrome P-450 and the dependent mono-oxygenase enzymes. Simultaneous administration of phenobarbital and endotoxin resulted in 100% mortality of rats. Combination of 3-methylcholanthrene and endotoxin did not block the induction of cytochrome P-448 or dependent benzo[a]pyrene hydroxylase activity. 5. Addition of endotoxin in vitro resulted in significant inhibition of hepatic microsomal cytochrome P-450 and aminopyrine N-demethylase activity only on preincubation with an NADPH-generating system supplemented with EDTA.
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PMID:Effects of endotoxin upon rat hepatic microsomal drug metabolism in vivo and in vitro. 713 99

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

We previously reported (Arch. Toxcol. 1998, 72, 492-498) that the differential decrease in the levels of hepatic cytochrome P450 (CYP) isozymes in rats was observed 24 hr after intracerebroventricular (i.c.v.) injection of bacterial lipopolysaccharide (LPS) at the dose ineffective (0.1 microgram) when injected intraperitoneally (i.p.). Among CYP isozymes we examined, the male specific CYP isozyme, CYP2C11 was most severely affected by i.c.v. injection of LPS. In this study, we examined the gene expression of CYP2C11, the total P450 contents, the CYP2C11-dependent activity of imipramine N-demethylase (IMND) and protein of CYP2C11 10 hr after i.c.v. or i.p. injections of LPS. Intracerebroventricular injection of LPS significantly decreased the level of CYP2C11 mRNA (to 63% of saline i.c.v. control), the total P450 contents (to 70% of saline i.c.v. control), the IMND activity (to 74% of saline i.c.v. control), but not protein of CYP2C11 in rat liver. In contrast, i.p. injection of LPS at the same dose as i.c.v. did not significantly affect these parameters. Since CYP is a heme protein, we also measured the activity of heme oxygenase (HO) using the same rat liver microsomes. The HO activity was increased to 166% by i.c.v. injection of LPS and 135% by i.p. injection of LPS compared to corresponding saline control. It is suggested that i.c.v. injection of LPS down-regulates the expression of CYP2C11 at transcriptional level and that both the decrease in CYP2C11 mRNA and the increase in heme degradation may be involved in the decreased level of protein and activity of CYP2C11 by i.c.v. injection of LPS in rat liver.
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PMID:Decrease in hepatic CYP2C11 mRNA and increase in heme oxygenase activity after intracerebroventricular injection of bacterial endotoxin. 1042 81

The effect of infection and inflammation of the central nervous system (CNS) on cytochrome-P450-dependent activities in brain, spinal cord and liver microsomes was determined. For this, two models were used: (1) the intracerebroventricularly injected lipopolysaccharide (LPS) model and (2) the experimental auto-immune encephalomyelitis (EAE) model. In the LPS model, aminopyrine N-demethylase (AMND) and ethoxycoumarin O-deethylase (ECOD) activities (both P450 dependent) were significantly decreased (35 and 20%, respectively) in brain microsomes. In the EAE model, only ECOD activity was significantly lower (18%). In the liver, a decrease in total P450, AMND and ECOD activities was only observed in the LPS model. In both models, tumour necrosis factor (TNF) was significantly elevated in brain and spinal cord tissues. In serum, TNF was only detectable in the LPS model. It is concluded that an infection or inflammation located in the CNS, which is accompanied by high TNF levels, results in a decrease in P450-dependent metabolism not only in the liver but in the brain as well.
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PMID:Decrease in brain cytochrome P450 enzyme activities during infection and inflammation of the central nervous system. 1112 80

Pregnane X receptor (PXR) is a member of the nuclear receptor superfamily that regulates target gene transcription in a ligand-dependent manner. The in vivo effects of lipopolysaccharide (LPS) on expression of PXR and its target gene cytochrome P450 3A (CYP3A) in mouse liver were investigated in this study. Mice were injected intraperitoneally with different doses of LPS (0.1-5.0 mg/kg). PXR and CYP3A11 mRNA levels were measured using reverse transcription polymerase chain reaction. Results indicate that LPS significantly inhibits the expression of PXR mRNA in a dose-dependent manner, followed by suppression of CYP3A11 mRNA in mouse liver. LPS also represses the upregulation of CYP3A11 mRNA levels and erythromycin N-demethylase (ERND) catalytic activity in mice pretreated with PXR ligands dexamethasone, rifampicin, mifepristone, and phenobarbital. LPS-induced downregulation of PXR and CYP3A11 mRNA in liver was significantly attenuated in mice pretreated with gadolinium chloride, a selective Kupffer cell toxicant. Pretreatment with a single dose of gadolinium chloride (10 mg/kg) also significantly attenuated LPS-induced downregulation of dexamethasone-, rifampicim-, mifepristone-, and phenobarbital-inducible, CYP3A11 mRNA expression and ERND activity in mouse liver. Furthermore, LPS-induced downregulation of PXR and CYP3A11 mRNA was significantly attenuated in mice pretreated with allopurinol, an inhibitor of xanthine oxidase, and diphenyleneiodonium chloride, an inhibitor of NADPH oxidase. Allopurinol and diphenyleneiodonium chloride pretreatment also attenuated the repressive effects of LPS on dexamethasone-, rifampicin-, mifepristone-, and phenobarbital-inducible CYP3A11 mRNA expression and ERND catalytic activity in mouse liver. However, aminoguanidine, a selective inhibitor of inducible nitric oxide synthase, has no effect on LPS-induced downregulation of PXR and CYP3A11 mRNA. Finally, LPS-induced downregulation of PXR and CYP3A11 mRNA was prevented in mice pretreated with either N-acetylcysteine or ascorbic acid. These antioxidants also prevented the repressive effects of LPS on dexamethasone-, rifampicin-, mifepristone-, and phenobarbital-inducible CYP3A11 mRNA expression and ERND catalytic activity in mouse liver. These results indicate that Kupffer cells contribute to LPS-induced downregulation of PXR and CYP3A in mouse liver. Reactive oxygen species, produced possibly by NADPH oxidase and perhaps by xanthine oxidase, are involved in LPS-induced downregulation of nuclear receptor PXR and its target gene CYP3A in mouse liver.
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PMID:Kupffer cells and reactive oxygen species partially mediate lipopolysaccharide-induced downregulation of nuclear receptor pregnane x receptor and its target gene CYP3a in mouse liver. 1518 91


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