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)

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.
 ...
PMID:Induction of cytochrome P450 2E1 expression in rat and gerbil astrocytes by inflammatory factors and ischemic injury. 891 36

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.
 ...
PMID:Endotoxin suppresses the oltipraz-mediated induction of major hepatic glutathione transferases and cytochromes P450 in the rat. 982 31

Hepatic cytochromes P-450 (CYP) are well characterized drug and xenobiotic metabolizing enzymes that are extensively regulated by genetic and environmental factors. Inflammatory mediators, including interleukins (ILs), interferons (IFNs), and tumor necrosis factor-alpha (TNF-alpha), have been shown to down-regulate several CYP isoforms; however, elucidation of the inflammatory mediators that are responsible for specific CYP down-regulation is difficult. The purpose of this experiment was to evaluate the role endogenous TNF-alpha plays in the regulation of liver CYP expression after endotoxin administration. Mice deficient in the p55 and p75 TNF receptors and wild-type mice were given Gram-negative bacterial lipopolysaccharide (LPS) and killed 24 h after administration. CYP analysis indicates that LPS decreases CYP1A, CYP2B, CYP3A, and CYP4A independently of TNF-alpha. CYP2D9 and CYP2E1 activities show differential responses to LPS between wild-type and TNF p55/p75 receptor knockout mice, indicating the down-regulation of CYP2D9 and CYP2E1 is differentially modulated by TNF-alpha expression. Furthermore, TNF-alpha appears to affect the constitutive expression of CYP2D9 and CYP2E1. To date, this is the first evidence suggesting that a proinflammatory cytokine is involved in the constitutive regulation of drug-metabolizing enzymes.
 ...
PMID:Hepatic cytochrome P-450 expression in tumor necrosis factor-alpha receptor (p55/p75) knockout mice after endotoxin administration. 1002 30

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.
 ...
PMID:The suppressive effects of lipopolysaccharide-induced acute phase response on hepatic cytochrome P450-dependent drug metabolism in rabbits. 1037 93

Most in vivo studies demonstrating decreased activities of hepatic cytochromes P450 with inflammation have used Gram-negative bacterial lipopolysaccharide (LPS) as the inflammatory stimulant. But products of Gram-positive bacteria, such as staphylococcal enterotoxin B (SEB), also stimulate inflammatory mediators, albeit with a different pattern than LPS. Therefore, effects of SEB on the regulation of murine constitutive P450s were determined in this study and compared with those of LPS. LPS-responsive C3H/HeN and LPS-unresponsive C3H/HeJ mice were injected with either LPS (0.5 mg/kg) or SEB (0.66 to 6.6 mg/kg), and hepatic cytochromes P450 and serum tumor necrosis factor-alpha, interleukin-6, nitrate/nitrite, and serum amyloid A concentrations were determined up to 24 hr. HeJ mice were generally less responsive than HeN mice to both stimuli, with lower cytokine, nitrate/nitrite, and serum amyloid A responses. However, in both mouse strains SEB caused more prolonged cytokine, higher nitrate/nitrite, and lower serum amyloid A concentrations than LPS. Despite these differences, in HeN mice, after both SEB and LPS administration, total P450 concentrations were equally depressed by 40%. Both SEB and LPS depressed CYP1A1 and 1A2 microsomal protein concentrations by 45 and 30%, respectively; CYP2E1 by 64%; and CYP3A by 70%. There was comparable inhibition of enzymatic activities. In HeJ mice, SEB was only slightly more effective in depressing P450s than LPS, as might be expected. These data showed that the Gram-positive bacterial inflammatory stimulant SEB caused effects on murine hepatic cytochromes P450 similar to those of LPS, even though the pattern of inflammatory mediators induced after SEB exposure was different.
 ...
PMID:Depression of constitutive murine cytochromes P450 by staphylococcal enterotoxin B. 1073 30

Expression of cytochromes P450 (CYP) is markedly reduced during inflammatory processes. In vitro studies with hepatocytes have shown that cytokines generated during these processes down-regulate CYP. However, it is not clear to what extent each individual cytokine contributes to the overall reduced expression of the various CYP isoenzymes in vivo. Interleukin 6 (IL-6), a major player during inflammatory processes, is recognized as the most important cytokine modulating the hepatic expression of acute-phase protein (APP) genes. For this reason, we selected the IL-6(-/-) mouse as a model to investigate the role of IL-6 in the down-regulation of hepatic CYP during experimental inflammation. Our results show that the reduction in messenger RNA (mRNA) levels of CYP1A2, CYP2A5, and CYP3A11 during turpentine-induced inflammation was abrogated in IL-6-deficient mice, confirming that IL-6 is an indispensable player for the down-regulation of hepatic CYP during aseptic inflammation. Moreover, the different CYP isoenzymes showed a variable grade of dependence on IL-6, CYP2A5 being the most sensitive one. In the case of CYP2E1, differences between IL-6(-/-) and wild-type mice were no longer maintained after 24 hours, suggesting a delayed, rather than abrogated, CYP down-regulation in the absence of IL-6. As opposed to that, hepatic CYP repression took place in IL-6-deficient mice during lipopolysaccharide (LPS)-mediated inflammation. This contrasting behavior observed for CYP is surprisingly similar to the one seen for extracellular (serum amyloid A, beta-fibrinogen) and intracellular (metallothionein-1) APPs and points to the fact that, in the model of bacterial inflammation (LPS), the effects of IL-6 on CYP down-regulation are likely to be substituted by other cytokines or mediators.
 ...
PMID:Hepatic cytochrome P450 down-regulation during aseptic inflammation in the mouse is interleukin 6 dependent. 1086 88

The effect of central nervous system inflammation on the levels and activity of hepatic and brain cytochrome P450 were examined in the rat. Brain ethoxyresorufin dealkylkase (EROD) was depressed during localized inflammatory responses evoked by lipopolysaccharide (LPS) injected into the lateral ventricle. This loss was accompanied by a concomitant loss of EROD activity and cytochrome P450 in liver. Similar losses in hepatic enzyme were observed for benzyloxy-resorufin and pentoxy-resorufin dealkylase (CYP2B) and chlorzoxazone hydroxylation (CYP2E). Protein levels of CYP2D and CYP2E1 but not CYP1A also were depressed. Similar i.p. doses of LPS had no effect on hepatic cytochrome P450, indicating that the hepatic effect was not caused by LPS leakage from the central nervous system. Also in support of this contention is that heat shock protein 27 was expressed throughout the brain by LPS given i.c. v. but was undetectable in the liver. Tumor necrosis factor-alpha given i.c.v. depressed EROD activity in the brain but this was not accompanied by a concomitant loss in the liver. Hepatic EROD did respond to the i.p. injection of tumor necrosis factor-alpha. The LPS-evoked loss in hepatic cytochrome P450 could not be prevented by blocking beta-receptor-mediated sympathetic nerve activity. This study demonstrates that localized inflammatory responses in the brain cause a concomitant down-regulation of cytochrome P450 and drug-metabolizing activity in the liver and the brain. The effect on brain cytochrome P450 may be regulated via cytokine-mediated pathways but signaling to the liver does not involve a cytokine-mediated pathway nor a beta-receptor-mediated sympathetic nerve pathway.
 ...
PMID:Hepatic and central nervous system cytochrome P450 are down-regulated during lipopolysaccharide-evoked localized inflammation in brain. 1090 Feb 28

The purpose of this study was to determine if changes in nuclear protein binding of hepatocyte nuclear factor 1 (HNF-1) occur after lipopolysaccharide (LPS) administration. In addition, the time-course of alterations in CYP2E1 regulation were evaluated. Rats were injected with 2.0 mg LPS and euthanized over a 72-h period. Nuclear protein binding to a consensus HNF-1 oligonucleotide was assessed by the electrophoretic mobility shift assay. CYP2E1 activity was analysed using chlorzoxazone as a substrate (60H-CLZ), and CYP2E1 protein concentration was determined by enzyme-linked immunosorbent assay. Endotoxin treatment resulted in decreased nuclear protein binding to an HNF-1 element as early as 1 h after treatment and returned to control levels by 72 h. This reduced binding persisted for 24 h and returned to control values 48 h after LPS administration. In addition, the reduction in binding was primarily attributable to a HNF-1alpha immunoreactive protein. The observed reduction in HNF-1 binding was followed in the time-course by decreases in CYP2E1 activity and protein content with maximal decreases to 50 and 67% of control, respectively, at 48 h after LPS administration. Endotoxin is a potent inducer of the acute phase response (APR). The APR stimulation by endotoxin administration reduced HNF-1alpha binding and decreased the expression of CYP2E1 in the rat liver. The time-course of alterations in HNF-1 and CYP2E1 lend support to the possibility that HNF-1alpha may play a role in the down-regulation of genes that require HNF-1alpha for their constitutive expression. These data serve as an important precedent for future studies evaluating the direct association of decreased HNF-1alpha binding and reduced gene expression after LPS administration.
 ...
PMID:The effect of endotoxin on hepatocyte nuclear factor 1 nuclear protein binding: potential implications on CYP2E1 expression in the rat. 1169 44

Hepatic cytochrome P450 (CYP) expression and antioxidant activity have been shown to decrease following endotoxin (lipopolysaccharide [LPS]) or proinflammatory cytokine administration. Using mice deficient in interleukin-6 (IL-6), the role of IL-6 in the regulation of hepatic CYP activity, glutathione (GSH) metabolism, and catalase (CAT) activity was analyzed after LPS administration. Administration of LPS produced comparable decreases in hepatic CYP3A activity in WT B6x129 (WT) mice and IL-6 knockout mice. No decrease was observed for CYP2D9 activity after LPS administration in either WT or IL-6 knockout mice. LPS administration significantly increased hepatic and renal CYP2E1 and CYP4A activity in WT mice, with no effect in IL-6 knockout mice. CYP2A12 activity increased in IL-6 knockout, mice with no change in WT mice after LPS administration. LPS administration had no significant effect on hepatic GSH reductase, GST peroxidase, GSH-S-transferase (GST), or total GSH in either WT or IL-6 knockout. However, hepatic CAT activity was significantly reduced in WT mice after LPS administration, with no effect in IL-6 knockout mice. These results support IL-6 as a critical mediator of the effects of LPS on specific hepatic and renal CYP activities and hepatic CAT activity.
 ...
PMID:Cytochrome P450 and antioxidant activity in interleukin-6 knockout mice after induction of the acute-phase response. 1171 Sep 94

Signal transducer and activator of transcription (Stat), a family of transcriptional factors, has been demonstrated to play a critical role in gene regulation in response to inflammatory cytokines, such as interferon and interleukin-6. Inflammatory cytokines and bacterial endotoxin are known to suppress, in most of cases, the constitutive or induced cytochromes P450 (P450) in animals and humans. However, it is not clear if the suppression of P450 by cytokines is through the Stat-signaling pathway. In the present study, we determined whether Stat1 is involved in lipopolysaccharide (LPS)-mediated modulation of P450 in mouse liver. In both Stat1(+/+) (wild type) and Stat1(-/-) (null) mice, a single dose of LPS treatment (1 mg/kg of body weight, i.p.) significantly reduced the expression of CYP3A11, 2C29, and 1A2 mRNA to 8 to 40% of the control levels as determined by real-time quantitative reverse transcription-polymerase chain reaction. The reduction was supported by Western blot analysis. In contrast, LPS significantly induced the level of CYP4A10 mRNA in both Stat1(+/+) (338% of control) and Stat1(-/-) mice (264% of control). Although suppression of mRNA levels of CYP2E1, and 2D9 was not observed in either LPS-treated Stat1 null or wild-type animals, LPS treatment resulted in a reduction of CYP2E1 protein content, which was more significant in Stat1(+/+) (23% of control) than in Stat1(-/-) mice (67% of control). Consistent with this result, the chlorzoxazone 6-hydroxylase and lauric acid 11-hydroxylase activities, as CYP2E1 representative activities, were reduced markedly by LPS in Stat1(+/+) but not in Stat1(-/-) mice. The ethoxyresorufin O-deethylase activity, as a representative CYP1A activity, was also reduced significantly only in LPS-treated Stat1(+/+) mice. These data clearly demonstrate that LPS-mediated modulation of CYP3A11, 2B10, 2C29, 1A2, and 4A10 in mouse liver is Stat1-independent. However, the significant difference between the LPS-treated Stat1(+/+) and Stat1(-/-) mice in the levels of CYP2E1 protein and activity as well as in the activity level of CYP1A suggests that Stat1 may be indirectly involved in the post-transcriptional modulation of these two mouse P450 enzymes.
 ...
PMID:Lipopolysaccharide-mediated modulation of cytochromes P450 in Stat1 null mice. 1264 64


1 2 3 Next >>