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)

It was reported that the hepatic microsomal cytochrome P450 (CYP) 2C11, 2D1, and 3A1 (not via the CYP1A2, 2B1/2, and 2E1) were involved in the metabolism of metformin in rats. It was also reported that the expressions of CYP2C11 and 3A2 decreased in rats pretreated with Klebsiella pneumoniae lipopolysaccharide (KPLPS). Therefore, the pharmacokinetic parameters of metformin could be changed in rats pretreated with KPLPS. Hence, the pharmacokinetic parameters of metformin were compared after both intravenous and oral administration of the drug at a dose of 100mg/kg to control rats and rats pretreated with KPLPS. After intravenous administration of metformin to rats pretreated with KPLPS, the total area under the plasma concentration-time curve from time 0 to infinity (AUC) of the drug was significantly greater (40.5% increase) than the controls due to significantly smaller CL value (27.7% decrease) than the controls. The significantly smaller CL value could be due to significantly smaller both the CL(R) and CL(NR) values (34.0% and 18.1% decrease, respectively) than the controls. The significantly smaller CL(NR) value could be due to decrease in the expressions of CYP2C11 and 3A2 in rats pretreated with KPLPS. After oral administration of metformin, the AUC of the drug was not significantly different between two groups of rats, and this may be at least partly due to decrease in absorption from the gastrointestinal tract compared with the controls.
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PMID:Effects of bacterial lipopolysaccharide on the pharmacokinetics of metformin in rats. 1727 28

We previously demonstrated that tumor necrosis factor alpha (TNF-alpha) and lipopolysaccharide (LPS) downregulate aryl hydrocarbon receptor (AhR)-regulated genes, such as cytochrome P450 1a1 (Cyp1a1) and NADPH: quinone oxidoreductase 1 (Nqo1) gene expression, yet the mechanisms involved remain unknown. The correlation between the inflammation-mediated suppression of AhR-regulated genes and the TNF-alpha or LPS-induced nitric oxide (NO) production especially in murine hepatoma Hepa 1c1c7 cells has been questioned; therefore we investigated whether NO is involved in the modulation of Cyp1a1 and Nqo1 by TNF-alpha or LPS in Hepa 1c1c7 cells. A significant dose-dependent increase in the inducible nitric oxide synthase (NOS2) expression and NO production were observed by various concentrations of TNF-alpha (1, 5, and 10 ng/mL) and LPS (1 and 5 microg/mL) which was completely inhibited by a NOS2 inhibitor, L-N6-(1-iminoethyl) lysine (L-NIL) (1 mM). Furthermore, TNF-alpha and LPS significantly induced NOS2 expression. Both TNF-alpha and LPS repressed the beta-naphthoflavone (betaNF)-mediated induction of Cyp1a1 and Nqo1 at mRNA and activity levels. The downregulation of Cyp1a1, but not Nqo1, was significantly prevented by L-NIL. However, proxynitrite decomposer, iron tetrakis (N-methyl-4'-pyridyl) porphyrinato (FeTMPyP) (5 microM) did not affect TNF-alpha- and LPS-mediated downregulation of Cyp1a1 and Nqo1 at mRNA and activity levels. These results show that NO, but not peroxynitrite, may be involved in TNF-alpha- and LPS-mediated downregulation of Cyp1a1 without affecting the downregulation of Nqo1.
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PMID:Role of nitric oxide in downregulation of cytochrome P450 1a1 and NADPH: Quinone oxidoreductase 1 by tumor necrosis factor-alpha and lipopolysaccharide. 1758 58

Pretreatment with a low dose of bacterial endotoxin (lipopolysaccharide, LPS) caused the reduction of cytochrome P450 (CYP) enzymes and inflammatory factors which are capable of protecting the liver from a lethal LPS challenge. However, the effects of LPS pretreatment on the expression of transforming growth factor beta1 (TGFbeta1) and leptin in thioacetamide (TAA)-induced liver fibrosis remain unknown. In this study, Sprague-Dawley rats were pretreated intraperitoneally with LPS (5 mg/kg body weight) for 24 h, and subsequently treated with TAA (200 mg/kg body weight/ 3 days) for 1 month to examine the effects of LPS on TAA-injured rats. LPS pretreatment was associated with lower granulation and lower (P < 0.05) GOT/GPT than in TAA-injured rats. The LPS-pretreated group had less collagen (Sirius red histochemical staining). Semiquantitative RT-PCR showed that the levels of collagen 3 and TGFbeta1 mRNAs were lower (P < 0.05) in the liver of LPS-pretreated rats than in TAA-injured rats. TGFbetaRI mRNA in the liver of LPS-pretreated rats exceeded (P < 0.05) that in TAA-injured rats. LPS pretreatment reduced the leptin content (Western blot) below that of TAA-injured rats. These results imply that LPS pretreatment (endotoxin tolerance) alleviates the TAA-induced liver fibrosis of rats by reducing TGFbeta1 and leptin content.
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PMID:Down-regulation of TGFbeta1 and leptin ameliorates thioacetamide-induced liver injury in lipopolysaccharide-primed rats. 1762 60

Exposure to inflammatory agents or cytokines causes the suppression of cytochrome P450 (CYP) enzyme activities and expression in liver and primary hepatocyte cultures. We showed previously that phenobarbital-induced CYP2B protein is down-regulated in primary cultures of rat hepatocytes after exposure to bacterial endotoxin (lipopolysaccharide) in a nitric oxide (NO) -dependent manner. In this study, we found that CYP2B proteins in primary rat hepatocyte cultures were suppressed >60% after 6 h of treatment with interleukin-1beta (IL-1). This effect was NO-dependent, and treatment of cells with the NO donors (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl) aminodiazen-1-ium-1,2-diolate (NOC-18), S-nitrosoglutathione, and S-nitroso-N-acetylpenicillamine also suppressed CYP2B proteins. However, the down-regulation by IL-1 was insensitive to inhibition of cGMP-dependent protein kinases. The down-regulation by IL-1 or NO donors was abolished by treatments with the proteasome inhibitors MG132 and lactacystin that did not affect NO production. The calpain inhibitor E64-d or the lysosomal protease inhibitors NH(4)Cl and chloroquine did not attenuate the down-regulation of CYP2B by IL-1. Treatment of HeLa cells expressing c-Myc-tagged CYP2B1 with NOC-18 down-regulated its expression and enhanced its ubiquitination. Treatment of rat liver microsomes with S-nitrosoglutathione caused S-nitrosylation of CYP2B protein and enhanced the ubiquitination pattern of CYP2B compared with unmodified CYP2B in an in vitro ubiquitination assay. These data are consistent with the hypothesis that NO-dependent CYP2B ubiquitination and proteasomal degradation are dependent on protein modification by reactive nitrogen species.
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PMID:Nitric oxide-dependent proteasomal degradation of cytochrome P450 2B proteins. 1799 47

Hepatic cytochrome P450 (P450) enzymes are down-regulated during inflammation. In this study, an animal model of inflammatory bowel disease was subjected to characterization of hepatic P450 expression under inflammatory conditions. Rats were treated intracolonically with 100 mg/kg trinitrobenzene sulfonic acid (TNBS) dissolved in 30% ethanol, and homogenates of colonic mucosa and hepatic microsomes of the rats were prepared. The colitis was accompanied by appearance of higher levels of portal endotoxin, interleukin-6, and nitric oxide metabolites and decreases in contents and activities for hepatic CYP3A2, CYP2C11, and, to a lesser extent, CYP1A2 and CYP2E1. Nimesulide, a preferential COX-2 inhibitor, protected rats with TNBS-induced colitis (TNBS-colitis) against the down-regulation of hepatic CYP3A2. Polymyxin B, which neutralizes endotoxin, curcumin, which has anti-inflammatory properties, and gadolinium chloride, which inactivates macrophages, attenuated the down-regulation of CYP3A2. Similar effects were observed in other P450s such as CYP2C11, but the agents were less effective in attenuating the down-regulation. Our data suggest that endogenous substances leaked from damaged colon in the rats with TNBS-colitis activate Kupffer cells, leading to down-regulation of hepatic P450s with differential susceptibility to the inflammatory stimuli. The colitis model, instead of exogenous administration of lipopolysaccharide or cytokines, could be applied to the study on mechanisms for altered hepatic P450 expression and other liver functions under mild inflammatory conditions.
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PMID:Down-regulation of hepatic cytochrome P450 enzymes in rats with trinitrobenzene sulfonic acid-induced colitis. 1807 64

It has been reported that telithromycin is metabolized primarily via hepatic microsomal cytochrome P450 (CYP) 3A1/2 in rats and that the expression of hepatic and intestinal CYP3A decreases in rats pretreated with Escherichia coli lipopolysaccharide (ECLPS rats; an animal model of inflammation). Thus, it is possible that the area under the plasma concentration-time curve from 0 h to infinity (AUC 0-infinity) of intravenous and oral telithromycin is greater for ECLPS rats than for the controls. To assess this, the pharmacokinetic parameters of telithromycin were compared after intravenous and oral administration (50 mg/kg). After intravenous administration of telithromycin, the AUC 0-infinity was significantly greater (by 83.4%) in ECLPS rats due to a significantly lower nonrenal clearance (by 44.5%) than in the controls. This may have been due to a significantly decreased hepatic metabolism of telithromycin in ECLPS rats. After oral administration of telithromycin, the AUC 0-infinity in ECLPS rats was also significantly greater (by 140%) than in the controls and the increase was considerably greater than the 83.4% increase after intravenous administration. This could have been due to a decrease in intestinal metabolism in addition to a decreased hepatic metabolism of telithromycin in ECLPS rats.
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PMID:Effects of Escherichia coli lipopolysaccharide on telithromycin pharmacokinetics in rats: inhibition of metabolism via CYP3A. 1816 May 19

Lipopolysaccharide (LPS) endotoxin is an active component in the outer membrane of Gram-negative bacteria. LPS is usually used as an animal model of chronic inflammation such as sepsis. During inflammation, development of diarrhea, and changes in the plasma protein bindings, in the hepatic and/or intestinal microsomal cytochrome P450 (CYP) isozymes, and in the renal excretion of drugs have been reported. Thus, in rats pretreated with lipopolysaccharide endotoxin isolated from Escherichia Coli (ECLPS rats), the absorption, the distribution, the metabolism, and the excretion of drugs could be expected to alter. Interestingly, in ECLPS rats, the time-dependent effects on the hepatic CYP isozymes have been reported. Thus, in ECLPS rats, the pharmacokinetics of drugs which are mainly metabolized via hepatic CYP isozymes could be expected to be time-dependent. In this review, an attempt to explain changes in the pharmacokinetics of drugs reported in the literature was made in terms of hepatic CYP isozyme changes or urinary excretion changes in ECLPS rats.
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PMID:Effects of endotoxin derived from Escherichia coli lipopolysaccharide on the pharmacokinetics of drugs. 1880 48

It has been reported that infection interferes with drug metabolism, resulting in changes in pharmacokinetics. In this study, we investigated the effects of lipopolysaccharide (LPS) on hepatic total cytochrome P450 (CYP), CYP3A2, and CYP2C11 contents in a transient, LPS-induced, endotoxemia model of rats. In addition, to assess the effects on CYP3A2 activities, the pharmacokinetics of midazolam (CYP3A2 substrate) and 1-OH-midazolam (metabolite of midazolam) were investigated. Hepatic total CYP contents were significantly low until day 3 (P < 0.05) but returned to the control level on day 5. Hepatic CYP3A2 contents were significantly decreased on day 1 until day 5 (P < 0.05) but returned to the control level on day 7. Hepatic CYP2C11 contents were continuously low until day 7, and lowest on day 3. The AUC of 1-OH-midazolam was significantly decreased on day 1 after LPS administration (P < 0.01). In conclusion, LPS (5 mg/kg) challenge decreased hepatic total CYP, CYP3A2, and CYP2C11 contents and also decreased the activities of hepatic CYP3A2. It took at least 7 days for hepatic total CYP and CYP3A2 to recover to control levels, and it was suggested that the changes of hepatic total CYP contents might correlate with those of hepatic CYP3A2 contents and activities. Additionally, it is shown that their changes might reflect the recovery process from inflammation.
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PMID:Changes of midazolam pharmacokinetics in Wistar rats treated with lipopolysaccharide: relationship between total CYP and CYP3A2. 1880 53

Epoxyeicosatrienoic acids (EETs) are derived from cytochrome P450-catalyzed epoxygenation of arachidonic acid and have emerged as important mediators of numerous biological effects. The major elimination pathway for EETs is through soluble epoxide hydrolase (sEH)-catalyzed metabolism to dihydroxyeicosatrienoic acids (DHETs). Based on previous studies showing that EETs have anti-inflammatory effects, we hypothesized that chronic inhibition of sEH would attenuate a lipopolysaccharide (LPS)-induced inflammatory response in vivo. Continuous dosing of the sEH inhibitors 12-(3-adamantan-1-ylureido)-dodecanoic acid (AUDA), a polyethylene glycol ester of AUDA, and 1-adamantan-1-yl-3-(5-(2-(2-ethoxyethoxy)ethoxy)-pentyl)urea resulted in robust exposure to the inhibitor and target engagement, as evidenced by significant increases in plasma EET/DHET ratios following 6 days of inhibitor treatment. However, sEH inhibitor treatment was not associated with an attenuation of LPS-induced inflammatory gene expression in the liver, and AUDA did not protect from LPS-induced neutrophil infiltration. Furthermore, Ephx2-/-mice that lack sEH expression and have significantly increased plasma EET/DHET ratios were not protected from LPS-induced inflammatory gene expression or neutrophil accumulation in the liver. LPS did have an effect on sEH expression and function, as evident from a significant down-regulation of Ephx2 mRNA and a significant shift in plasma EET/DHET ratios 4 h after LPS treatment. In conclusion, there was no evidence that increasing EET levels in vivo could modulate an LPS-induced inflammatory response in the liver. However, LPS did have significant effects on plasma eicosanoid levels and hepatic Ephx2 expression, suggesting that in vivo EET levels are modulated in response to an inflammatory signal.
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PMID:Inhibition of soluble epoxide hydrolase does not protect against endotoxin-mediated hepatic inflammation. 1881 52

The transcription and protein expression of many cytochrome P450 (P450) genes are down-regulated in animal models of inflammation and infection. We determined previously that hepatic P450 mRNAs are selectively regulated in a mouse model of enteropathogenic bacterial infection, and that this regulation was not dependent on the lipopolysaccharide (LPS) receptor protein toll-like receptor 4 (TLR4). In the dextran sulfate sodium (DSS) model of chemically induced inflammatory bowel disease (IBD), the reduction in activities of several hepatic P450 enzymes were concluded to be partially dependent on LPS from commensal bacteria [Masubuchi Y, Horie T. Endotoxin-mediated disturbance of hepatic cytochrome P450 function and development of endotoxin tolerance in the rat model of dextran sulfate sodium-induced experimental colitis. Drug Metab Dispos 2004;32:437-441]. In the present study, we sought to determine whether colitis induced by LPS regulates hepatic P450 mRNA and protein expression similarly to infectious colitis, and to determine the role of TLR4 in the response to DSS colitis. The role of LPS in the response to DSS was further examined by comparison with the effects of injected LPS. We demonstrate that administration of DSS results in the down-regulation of multiple P450 enzymes in mouse liver. However, there are discernable differences in the pattern of P450 expression in the two models. Some effects of DSS-induced colitis are TLR4-dependent, and others are not. In contrast, the effects of injected LPS on hepatic P450 mRNA expression are entirely TLR4-dependent. Thus, our results indicate that the pattern of hepatic P450 expression, and the mechanism of regulation, during inflammation of the bowel depend on the etiology of the disease.
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PMID:TLR4-dependent and -independent regulation of hepatic cytochrome P450 in mice with chemically induced inflammatory bowel disease. 1902 21


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