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)

Recent studies have demonstrated that macrophages are the cell types capable of metabolizing benzo[a]pyrene (B(a)P) within the spleens of untreated mice. Since repeated exposure to B(a)P results in immunosuppression and B(a)P is known to induce cytochrome P450 levels, the first objective of this study was to investigate whether exposure of mice to B(a)P could increase the amounts of immunosuppressive B(a)P metabolites generated and/or alter the pattern of B(a)P metabolites formed by several different splenic cell types. Mice were dosed with a daily sc dose of 200 mg/kg B(a)P or vehicle for 4 days. Separation of splenocytes based on density by centrifugation through discontinuous Percoll gradients along with immunomagnetic negative selection or antibody-mediated complement lysis was used to obtain different splenic cell populations. Cells were incubated with [3H]B(a)P for 24 hr. High-pressure liquid chromatography was used to separate and quantitate B(a)P metabolites. Results indicate that splenic macrophages of B(a)P-treated mice produced significantly greater amounts of some metabolites compared to those of vehicle-treated mice. The three major metabolites produced were an unidentified peak of polar metabolites containing polyhydroxylated metabolites, B(a)P-9,10- and B(a)P-7,8-dihydrodiols. Other splenic cell types examined did not produce metabolite amounts significantly above (T-cells, PMNs, or the capsule) or just above (B-cells) background. The second objective was to investigate the splenic cell type(s) targeted by B(a)P resulting in suppression of humoral immunity. Separation-reconstitution studies along with in vitro sensitization techniques with several different antigens (sheep red blood cells (SRBC), dinitrophenyl-Ficoll (DNP-Ficoll), lipopolysaccharide (LPS)) were used to identify splenic target cells following exposure of mice to B(a)P (200 mg/kg/day, sc for 4 days). Findings indicate that in vitro plaque-forming cell (PFC) suppression was due to alterations in the adherent (macrophage) cell population. Exposure also suppressed the PFC response to the T-dependent antigen SRBC and the T-independent antigen DNP-Ficoll, but did not suppress the PFC response to the polyclonal antigen, LPS. These data suggest that B(a)P is targeting macrophages.
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PMID:Evaluation of murine splenic cell type metabolism of benzo[a]pyrene and functionality in vitro following repeated in vivo exposure to benzo[a]pyrene. 141 70

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 biphasic behaviour observed in endotoxin-induced shock attributed to a direct interaction of bacterial lipopolysaccharides with the cell membrane and an indirect activation of multiple homeostatic regulatory mechanisms, cannot be completely elucidated with in vivo studies. In primary cultures of adult rat hepatocytes, lipopolysaccharide from Escherichia coli 0111:B4 affects the cytochrome P450 levels directly; however, albumin and aspartate aminotransferase secretion are induced by some mediators present in the sera of animals in acute-phase shock.
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PMID:Direct and mediated Escherichia coli lipopolysaccharide action in primary hepatocyte cultures. 329 5

The isolated perfused kidney of the rat was used to examine the hypothesis that lipopolysaccharide-induced nitric oxide (NO) production inhibits cytochrome P450-dependent vasodilation. The vasodilator responses to arachidonic acid and bradykinin were examined as the response to arachidonic acid is wholly dependent, and that to bradykinin partly dependent on cytochrome P450 metabolism. In endotoxin-treated rats, the vasodilator response to arachidonic acid was inhibited, and those to bradykinin and acetylcholine were enhanced. Following treatment with phenobarbitone, the inducer of certain isoforms of cytochrome P450 enzymes, the vasodilator effects of all three agonists, especially that of arachidonic acid, were amplified. Lipopolysaccharide inhibited the effect of phenobarbitone on the vasodilator effect of arachidonic acid and bradykinin but enhanced that of acetylcholine. The effect of lipopolysaccharide was antagonized by haemoglobin, a NO antagonist, and N omega-nitro-L-arginine, an inhibitor of NO synthase, suggesting that the inhibitory effect of lipopolysaccharide on arachidonic acid- and bradykinin-induced vasodilation was mediated by NO/NO synthase. N omega-Nitro-L-arginine enhanced vasodilation induced by arachidonic acid while that induced by bradykinin or acetylcholine was reduced, implying that endogenous NO inhibits vasodilator cytochrome P450 metabolites in the rat kidney. Pretreatment with dexamethasone, an inhibitor of inducible NO synthase, resulted in inhibition of the lipopolysaccharide modulation of arachidonic acid-induced vasodilation, suggesting that the inducible NO synthase is the target of the inhibitory effect of lipopolysaccharide. The inhibitory effect of lipopolysaccharide was mimicked by nitroprusside, the L-arginine-independent NO donor, and by L-arginine, the biosynthetic precursor of NO. The effect of L-arginine, but not of nitroprusside, was antagonized by N omega-nitro-L-arginine, suggesting a specific role for NO synthase in the inhibitory effect of lipopolysaccharide in the inhibition of cytochrome P450-dependent vasodilation in the rat kidney.
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PMID:The suppression by lipopolysaccharide of cytochrome P450-dependent renal vasodilation in the rat is mediated by nitric oxide. 749 99

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.
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PMID:Nitric oxide is a mediator of the decrease in cytochrome P450-dependent metabolism caused by immunostimulants. 750 96

Enhanced formation of nitric oxide (NO) by both the constitutive and the inducible isoforms of NO synthase (NOS) has been implicated in the pathophysiology of a variety of diseases, including circulatory shock. Non-isoform-selective inhibition of NO formation, however, may lead to side effects by inhibiting the constitutive isoform of NOS and, thus, the various physiological actions of NO. S-Methylisothiourea sulfate (SMT) is at least 10- to 30-fold more potent as an inhibitor of inducible NOS (iNOS) in immunostimulated cultured macrophages (EC50, 6 microM) and vascular smooth muscle cells (EC50, 2 microM) than NG-methyl-L-arginine (MeArg) or any other NOS inhibitor yet known. The effect of SMT on iNOS activity can be reversed by excess L-arginine in a concentration-dependent manner. SMT (up to 1 mM) does not inhibit the activity of xanthine oxidase, diaphorase, lactate dehydrogenase, monoamine oxidase, catalase, cytochrome P450, or superoxide dismutase. SMT is equipotent with MeArg in inhibiting the endothelial, constitutive isoform of NOS in vitro and causes increases in blood pressure similar to those produced by MeArg in normal rats. SMT, however, dose-dependently reverses (0.01-3 mg/kg) the hypotension and the vascular hyporeactivity to vasoconstrictor agents caused by endotoxin [bacterial lipopolysaccharide (LPS), 10 mg/kg, i.v.] in anesthetized rats. Moreover, therapeutic administration of SMT (5 mg/kg, i.p., given 2 hr after LPS, 10 mg/kg, i.p.) attenuates the rises in plasma alanine and aspartate aminotransferases, bilirubin, and creatinine and also prevents hypocalcaemia when measured 6 hr after administration of LPS. SMT (1 mg/kg, i.p.) improves 24-hr survival of mice treated with a high dose of LPS (60 mg/kg, i.p.). Thus, SMT is a potent and selective inhibitor of iNOS and exerts beneficial effects in rodent models of septic shock. SMT, therefore, may have considerable value in the therapy of circulatory shock of various etiologies and other pathophysiological conditions associated with induction of iNOS.
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PMID:Beneficial effects and improved survival in rodent models of septic shock with S-methylisothiourea sulfate, a potent and selective inhibitor of inducible nitric oxide synthase. 752 23

Dexamethasone (DEX) is a well-known inhibitor of tumor necrosis factor (TNF) production when given shortly before lipopolysaccharide (LPS). However, DEX (10 mg/kg, ip) potentiates TNF production when administered 24-48 hr before LPS (16 micrograms/kg, ip). We have found that this is probably due to DEX induction of cytochrome P450 3A, which is known to produce nitric oxide (NO). The upregulating effect of DEX on TNF production is associated with increased NO production. Both the upregulation of NO and of TNF production by DEX are inhibited by co-administration of the P450 3A inhibitor troleandomycin (TAO, 40 mg/kg, ip). These data suggest that P450 3A-generated NO might be involved in TNF induction.
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PMID:The upregulating effect of dexamethasone on tumor necrosis factor production is mediated by a nitric oxide-producing cytochrome P450. 772 92

Treatment of mice with Corynebacterium parvum induces chronic inflammation. This treatment followed by an injection of lipopolysaccharide (LPS) produces hepatic necrosis and death. We examined liver tissue by using electron paramagnetic resonance (EPR) spectroscopy and found that, in addition to the previously reported nonheme nitrosyl complexes, heme nitrosyl complexes were also formed. Hemoglobin nitrosyl complexes measured in the whole blood of mice treated with C. parvum were not increased after additional LPS treatment. However, this treatment significantly increased the heme nitrosyl complexes in the liver, whereas the nonheme nitrosyl complex concentration was unaffected. EPR signals from whole blood and liver tissues from mice treated with C. parvum and C. parvum + LPS were inhibited by prolonged treatment with NG-monomethyl-L-arginine (L-NMA). Nitric oxide (.NO) is known to bind to cytochrome P450 heme, and we consistently found a suppression of EPR signals attributable to ferric low-spin cytochrome P450/P420 peaks in the livers of mice treated with C. parvum and C. parvum + LPS. By performing analyses of EPR spectra obtained from hepatocytes exposed to .NO, we were able to unambiguously identify EPR signals attributable to cytochrome P420 and nonheme nitrosyl complexes in the livers of both treatments. Deconvolution of the composite in vivo EPR spectra indicated that hemoglobin nitrosyl complexes contributed weakly in the C. parvum livers, but threefold more in the C. parvum + LPS livers, suggesting that hemorrhage may have occurred. Experiments with L-NMA treatment revealed that this additional .NO production did not correlate with hepatic necrosis and onset of death. Immunoprecipitation of liver cytosols from C. parvum- and (C. parvum + LPS)-treated mice using an antibody against mouse inducible nitric oxide synthase showed that this enzyme was indeed present in the cytosolic fractions and was absent in those from control livers. Our novel detection of cytochrome P420 nitrosyl complex in vivo may be linked to any role of hepatic P450's functions during liver inflammation.
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PMID:Targets of nitric oxide in a mouse model of liver inflammation by Corynebacterium parvum. 784 Jun 29

To determine the influence of insulin-like growth factor-1 (IGF-1) on nitrogen loss and hepatic response to critical illness, 34 male Sprague-Dawley rats (190-230 g) were randomized to receive parenteral nutrition (PN) only (Ctrl), PN plus continuous infusion of Escherichia coli 026:B6 lipopolysaccharide at 6 mg/kg/day (LPS), or PN plus LPS plus rhIGF-1 (IGF-1) at 3 mg/kg/day for 48 hr. Prior to randomization, all animals underwent iv cannulation and 30 hr of adaptation to PN. All animals received isocaloric and isonitrogenous PN (glucose 170 kcal/kg/day and nitrogen 1.1 g/kg/day) and were kept NPO except for water ad libitum. [15N]glycine was infused in all animals for determination of liver fractional synthetic rate. Cumulative nitrogen balance during endotoxemia was significantly different from each other (+72 +/- 42, -217 +/- 131, -114 +/- 137 mg/kg/48 hr for the Ctrl, LPS, and IGF-1 groups, respectively; ANOVA, P < 0.001). Endotoxin significantly increased the urinary 3-methylhistidine/creatinine ratio (0.24 +/- 0.05, 0.55 +/- 0.12, 0.48 +/- 0.17 for the Ctrl, LPS, and IGF-1 groups, respectively; ANOVA, P < 0.001); however, IGF-1 did not significantly reduce the ratio. Endotoxin induced a significant increase in liver fractional synthetic rate (29 +/- 8, 56 +/- 18, 64 +/- 12%/day for the Ctrl, LPS, and IGF-1 groups, respectively; ANOVA, P < 0.01) and depressed hepatic cytochrome P450 concentration (0.54 +/- 0.19, 0.22 +/- 0.07, 0.19 +/- 0.07 nmol/mg protein, respectively; ANOVA, P < 0.05) and ethoxycoumarin O-deethylase (ECOD) activity (103 +/- 73, 29 +/- 13, 17 +/- 11, pmol/mg/min, respectively; ANOVA, P < 0.01); however, rhIGF-1 did not significantly alter these hepatic variables during endotoxin infusion. Recombinant human insulin-like growth factor-1 significantly improved nitrogen balance without compromising hepatic response as measured by liver fractional synthetic rate, cytochrome P450 concentration, and ECOD activity in endotoxemic parenterally fed rats.
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PMID:The effect of insulin-like growth factor-1 on protein metabolism and hepatic response to endotoxemia in parenterally fed rats. 788 22


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