RESUMEN
AUY922, a heat shock protein 90 inhibitor is associated with ocular adverse events (AEs). To provide a better understanding of ocular AEs in patients, 4 investigative studies were performed in a step-wise approach to assess retinal structure and function in pigmented (Brown Norway) and albino (Wistar) rats. In rats administered 30mg/kg of AUY922, the AUC0-24h and Cmax are comparable to that in patients at 70mg/m(2). AUY922 at ≥30mg/kg was poorly tolerated by rats with morbidity or mortality generally after the third weekly treatment. Electroretinography (ERG) changes were observed at doses ≥30mg/kg. The ERG changes were dose dependent, consistent with an effect on the photoreceptors, and fully reversible. The ERG effects could not be minimized by decreasing the Cmax while maintaining AUC. Histopathological changes were seen mainly when rats were administered AUY922 at 100mg/kg. The 2-hour infusion of AUY922 at 100mg/kg caused disorganization of the outer segment photoreceptor morphology in male Brown Norway rats; the severity of the disorganization increased with the number of administrations, but was reversible during a 4-week posttreatment period. There was no major difference in ocular response between Brown Norway and Wistar rats. No changes in serum iron levels, and no changes in rhodopsin, PDE6α, ß-transducin concentrations, or retinal pigment epithelium-specific protein RPE65 expression were observed after single and multiple infusions of AUY922 at 100mg/kg compared to vehicle-treated controls. AUY922 retinal toxicity in rats recapitulates and further characterizes that reported in patients and is shown to be reversible, while a precise molecular mechanism for the effect was not determined.
Asunto(s)
Ojo/efectos de los fármacos , Animales , Electrorretinografía , Ojo/fisiopatología , Isoxazoles/toxicidad , Ratas , Ratas Wistar , Resorcinoles/toxicidadRESUMEN
To investigate the pathogenic mechanism of ulcerative colitis, a dextran sulfate sodium (DSS)-induced acute colitis model was examined by serum metabolomic analysis. Higher levels of stearoyl lysophosphatidylcholine and lower levels of oleoyl lysophosphatidylcholine in DSS-treated mice compared to controls led to the identification of DSS-elicited inhibition of stearoyl-CoA desaturase 1 (SCD1) expression in liver. This decrease occurred prior to the symptoms of acute colitis and was well correlated with elevated expression of proinflammatory cytokines. Furthermore, Citrobacter rodentium-induced colitis and lipopolysaccharide treatment also suppressed SCD1 expression in liver. Scd1 null mice were more susceptible to DSS treatment than wild-type mice, while oleic acid feeding and in vivo SCD1 rescue with SCD1 adenovirus alleviated the DSS-induced phenotype. This study reveals that inhibition of SCD1-mediated oleic acid biogenesis exacerbates proinflammatory responses to exogenous challenges, suggesting that SCD1 and its related lipid species may serve as potential targets for intervention or treatment of inflammatory diseases.
Asunto(s)
Colitis/etiología , Regulación hacia Abajo , Inflamación/etiología , Metabolismo de los Lípidos/fisiología , Hígado/metabolismo , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Animales , Sulfato de Dextran , Modelos Animales de Enfermedad , Ratones , Fosfatidilcolinas/análisis , Estearoil-CoA Desaturasa/deficienciaRESUMEN
Microsomal enzyme inducers (MEI) that increase UDP-glucuronosyltransferases (UGTs) are thought to increase glucuronidation of thyroxine (T(4)), thus reducing serum T(4), and subsequently increasing thyroid stimulating hormone (TSH). Ugt1a1 and Ugt1a6 mediate T(4) glucuronidation. Therefore, this experiment determined the involvement of Ugt1a enzymes in increased T(4) glucuronidation, decreased serum T(4), and increased TSH after MEI treatment. Male Wistar and Ugt1a-deficient Wistar (Gunn) rats were fed a control diet or diet containing pregnenolone-16α-carbonitrile (PCN; 800 ppm), 3-methylcholanthrene (3-MC; 200 ppm), or Aroclor 1254 (PCB; 100 ppm) for 7 days. Serum T(4), triiodothyronine (T(3)), and TSH concentrations, hepatic T(4)/T(3) glucuronidation, and thyroid histology and follicular cell proliferation were investigated. PCN, 3-MC, and PCB treatments decreased serum T(4), whereas serum T(3) was maintained in both Gunn and Wistar rats (except for PCB treatment). TSH was increased in Wistar and Gunn rats after PCN (130 and 277%) or PCB treatment (72 and 60%). T(4) glucuronidation in Wistar rats was increased after PCN (298%), 3-MC (85%), and PCB (450%), but was extremely low in Gunn rats, and unchanged after MEI. T(3) glucuronidation was increased after PCN (121%) or PCB (58%) in Wistar rats, but only PCN increased T(3) glucuronidation in Gunn rats (43%). PCN treatment induced thyroid morphological changes and increased follicular cell proliferation in both strains. These data demonstrate that T(4) glucuronidation cannot be increased in Ugt1a-deficient Gunn rats. Thus, the decrease in serum T(4), increase in TSH, and increase in thyroid cell proliferation after MEI are not dependent on increased T(4) glucuronidation, and cannot be attributed to Ugt1a enzymes.
Asunto(s)
/toxicidad , Glucuronosiltransferasa/efectos de los fármacos , Metilcolantreno/toxicidad , Carbonitrilo de Pregnenolona/toxicidad , Animales , Proliferación Celular/efectos de los fármacos , Glucuronosiltransferasa/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Ratas , Ratas Gunn , Ratas Wistar , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/enzimología , Tirotropina/sangre , Tiroxina/efectos de los fármacos , Tiroxina/metabolismo , Triyodotironina/sangreRESUMEN
The objective of the study was to investigate the regulation of hepatic flavin-containing monooxygenases (Fmo) Fmo1, Fmo3, Fmo4, and Fmo5 in three different mouse models of inflammation, including treatment with Citrobacter rodentium, lipopolysaccharide (LPS), and dextran sulfate sodium (DSS). Quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) was used to evaluate the steady-state mRNA levels for the various Fmo isoforms in these mouse models of inflammation during different treatment time courses. Fmo3 mRNA was most significantly down-regulated in C. rodentium-treated female mice. Fmo1, Fmo3, and Fmo5 mRNAs were also found to be down-regulated in LPS models of inflammation. The significant down-regulation of hepatic FMO3 protein during C. rodentium treatment was confirmed with Western blot analysis of liver microsomes from treated animals. Toll-like receptor (TLR) 4 is known to be responsible for LPS signaling in association with several proteins. To investigate whether TLR4 was responsible for regulation of Fmo genes in both LPS and C. rodentium animal models, Fmo mRNA levels in female wild-type (C3H/HeOuJ) and TLR4 mutant (C3H/HeJ) mice were compared in both inflammatory models by real-time RT-PCR. The results showed that Fmo3 down-regulation during C. rodentium infection is independent of TLR4. Whereas TLR4 is likely to play only a partial role in Fmo1 gene regulation in LPS-treated animals, our results show that the down-regulation of Fmo3 and Fmo5 in this model is TLR4-dependent. Unlike cytochrome P450 regulation measured in the same mouse strains, Fmo3 expression was largely refractory to down-regulation in the DSS model of inflammatory colitis.
Asunto(s)
Modelos Animales de Enfermedad , Regulación Enzimológica de la Expresión Génica , Inflamación/genética , Hígado/enzimología , Oxigenasas/genética , Animales , Secuencia de Bases , Western Blotting , Cartilla de ADN , Sulfato de Dextran/toxicidad , Femenino , Inflamación/inducido químicamente , Inflamación/enzimología , Lipopolisacáridos/toxicidad , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , ARN Mensajero/genética , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/fisiologíaRESUMEN
We reported previously that infection of C3H/HeOuJ (HeOu) mice with the murine intestinal pathogen Citrobacter rodentium caused a selective modulation of hepatic cytochrome P450 (P450) gene expression in the liver that was independent of the Toll-like receptor 4. However, HeOu mice are much more sensitive to the pathogenic effects of C. rodentium infection, and the P450 down-regulation was associated with significant morbidity in the animals. Here, we report that oral infection of C57BL/6 mice with C. rodentium, which produced only mild clinical signs and symptoms, produced very similar effects on hepatic P450 expression in this strain. As in HeOu mice, CYP4A mRNAs and proteins were among the most sensitive to down-regulation, whereas CYP4F18 was induced. CYP2D9 mRNA was also induced 8- to 9-fold in the C57BL/6 mice. The time course of P450 regulation followed that of colonic inflammation and bacterial colonization, peaking at 7 to 10 days after infection and returning to normal at 15 to 24 days as the infection resolved. These changes also correlated with the time course of significant elevations in the serum of the proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor-alpha, as well as of interferon-gamma and IL-2, with serum levels of IL-6 being markedly higher than those of the other cytokines. Intraperitoneal administration of C. rodentium produced a rapid down-regulation of P450 enzymes that was quantitatively and qualitatively different from that of oral infection, although CYP2D9 was induced in both models, suggesting that the effects of oral infection on the liver are not due to bacterial translocation.
Asunto(s)
Citrobacter rodentium , Sistema Enzimático del Citocromo P-450/metabolismo , Infecciones por Enterobacteriaceae/enzimología , Regulación Enzimológica de la Expresión Génica , Microsomas Hepáticos/enzimología , Sepsis/metabolismo , Animales , Fenómenos Biológicos , Sistema Enzimático del Citocromo P-450/genética , Modelos Animales de Enfermedad , Infecciones por Enterobacteriaceae/genética , Infecciones por Enterobacteriaceae/metabolismo , Femenino , Mucosa Intestinal/metabolismo , Intestinos/microbiología , Intestinos/patología , Hígado/enzimología , Hígado/metabolismo , Hígado/microbiología , Ratones , Ratones Endogámicos BALB C , Microsomas Hepáticos/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Sepsis/enzimologíaRESUMEN
This article is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 07 meeting in Washington, DC. The presentations discussed the phenomenology, clinical consequences, and underlying mechanisms of cytochrome P450 and drug transporter regulation by inflammatory and infectious stimuli. Although considerable insights into the links between inflammatory mediators and altered hepatic drug clearance pathways have been gained from previous studies with acute inflammatory stimuli, this symposium highlighted recent advances in understanding how these processes operate in other organs and chronic inflammatory states relevant to human diseases. The development of mouse models of live bacterial infection provides excellent opportunities to explore the impact of infection on drug metabolism beyond the well characterized effects of bacterial endotoxin. Altered levels of cytochromes P450 and especially drug transporters due to inflammation in brain, intestine, and placenta have significant implications for the use of many drugs in diverse clinical settings. The consequences of inflammatory cytokine production by tumors for drug safety and efficacy in cancer patients were outlined. Repression of drug clearance pathways by tumor-derived cytokines may result in extreme toxicity to chemotherapy, compromising treatment of many cancers. It is fitting that, in honoring the career contributions and achievements of Dr. Kenneth W. Renton, this symposium reinforced the clinical relevance of this field.
Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Infecciones/metabolismo , Inflamación/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Neoplasias/metabolismo , Animales , Sistema Enzimático del Citocromo P-450/genética , Humanos , Preparaciones Farmacéuticas/metabolismo , Transcripción GenéticaRESUMEN
The FGF19- fibroblast growth factor receptor (FGFR4)-ßKlotho (KLB) pathway plays an important role in the regulation of bile acid (BA) homeostasis. Aberrant activation of this pathway has been described in the development and progression of a subset of liver cancers including hepatocellular carcinoma, establishing FGFR4 as an attractive therapeutic target for such solid tumors. FGF401 is a highly selective FGFR4 kinase inhibitor being developed for hepatocellular carcinoma, currently in phase I/II clinical studies. In preclinical studies in mice and dogs, oral administration of FGF401 led to induction of Cyp7a1, elevation of its peripheral marker 7alpha-hydroxy-4-cholesten-3-one, increased BA pool size, decreased serum cholesterol and diarrhea in dogs. FGF401 was also associated with increases of serum aminotransferases, primarily alanine aminotransferase (ALT), in the absence of any observable adverse histopathological findings in the liver, or in any other organs. We hypothesized that the increase in ALT could be secondary to increased BAs and conducted an investigative study in dogs with FGF401 and coadministration of the BA sequestrant cholestyramine (CHO). CHO prevented and reversed FGF401-related increases in ALT in dogs in parallel to its ability to reduce BAs in the circulation. Correlation analysis showed that FGF401-mediated increases in ALT strongly correlated with increases in taurolithocholic acid and taurodeoxycholic acid, the major secondary BAs in dog plasma, indicating a mechanistic link between ALT elevation and changes in BA pool hydrophobicity. Thus, CHO may offer the potential to mitigate elevations in serum aminotransferases in human subjects that are caused by targeted FGFR4 inhibition and elevated intracellular BA levels.
Asunto(s)
Alanina Transaminasa/sangre , Ácidos y Sales Biliares/sangre , Resina de Colestiramina/farmacología , Hígado/efectos de los fármacos , Inhibidores de Proteínas Quinasas/toxicidad , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Alanina Transaminasa/biosíntesis , Animales , Ácidos y Sales Biliares/biosíntesis , Perros , Relación Dosis-Respuesta a Droga , Femenino , Hígado/enzimología , Masculino , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/sangre , Piridinas/farmacología , Pruebas de Toxicidad , ToxicocinéticaRESUMEN
Microsomal enzyme inducers (MEI) that increase UDP-glucuronosyltransferases (UGTs) can impact thyroid hormone homeostasis in rodents. Increased glucuronidation can result in reduction of serum thyroid hormone and a concomitant increase in thyroid-stimulating hormone (TSH). UGT2B2 is thought to glucuronidate triiodothyronine (T(3)). The purposes of this study were to determine the role of UGT2B2 in T(3) glucuronidation and whether increased T(3) glucuronidation mediates the increased TSH observed after MEI treatment. Sprague Dawley (SD) and UGT2B2-deficient Fischer 344 (F344) rats were fed a control diet or diet containing pregnenolone-16alpha-carbonitrile (PCN; 800 ppm), 3-methylcholanthrene (3-MC; 200 ppm), or Aroclor 1254 (PCB; 100 ppm) for 7 days. Serum thyroxine (T(4)), T(3), and TSH concentrations, hepatic androsterone/T(4)/T(3) glucuronidation, and thyroid follicular cell proliferation were determined. In both SD and F344 rats, MEI treatments decreased serum T(4), whereas serum T(3) was maintained (except with PCB treatment). Hepatic T(4) glucuronidation increased significantly after MEI in both rat strains. Compared with the other MEI, only PCN treatment significantly increased T(3) glucuronidation (281 and 497%) in both SD and UGT2B2-deficient F344 rats, respectively, and increased both serum TSH and thyroid follicular cell proliferation. These data demonstrate an association among increases in T(3) glucuronidation, TSH, and follicular cell proliferation after PCN treatment, suggesting that T(3) is glucuronidated by other PCN-inducible UGTs in addition to UGT2B2. These data also suggest that PCN (rather than 3-MC or PCB) promotes thyroid tumors through excessive TSH stimulation of the thyroid gland.
Asunto(s)
Glucuronosiltransferasa/fisiología , Triyodotironina/metabolismo , Androsterona/metabolismo , Animales , Inducción Enzimática/efectos de los fármacos , Glucurónidos/metabolismo , Glucuronosiltransferasa/deficiencia , Masculino , Microsomas/enzimología , Carbonitrilo de Pregnenolona/farmacología , Ratas , Ratas Endogámicas F344 , Ratas Sprague-Dawley , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/patología , Tirotropina/sangreRESUMEN
BACKGROUND/AIMS: The Peroxisome Proliferator-Activated Receptor (PPAR) alpha belongs to the superfamily of Nuclear Receptors and plays an important role in numerous cellular processes, including lipid metabolism. It is known that PPARalpha also has an anti-inflammatory effect, which is mainly achieved by down-regulating pro-inflammatory genes. The objective of this study was to further characterize the role of PPARalpha in inflammatory gene regulation in liver. RESULTS: According to Affymetrix micro-array analysis, the expression of various inflammatory genes in liver was decreased by treatment of mice with the synthetic PPARalpha agonist Wy14643 in a PPARalpha-dependent manner. In contrast, expression of Interleukin-1 receptor antagonist (IL-1ra), which was acutely stimulated by LPS treatment, was induced by PPARalpha. Up-regulation of IL-1ra by LPS was lower in PPARalpha -/- mice compared to Wt mice. Transactivation and chromatin immunoprecipitation studies identified IL-1ra as a direct positive target gene of PPARalpha with a functional PPRE present in the promoter. Up-regulation of IL-1ra by PPARalpha was conserved in human HepG2 hepatoma cells and the human monocyte/macrophage THP-1 cell line. CONCLUSIONS: In addition to down-regulating expression of pro-inflammatory genes, PPARalpha suppresses the inflammatory response by direct up-regulation of genes with anti-inflammatory properties.
Asunto(s)
Hepatitis/genética , Proteína Antagonista del Receptor de Interleucina 1/metabolismo , Hígado/metabolismo , PPAR alfa/metabolismo , Factores de Transcripción/metabolismo , Animales , Anticolesterolemiantes/farmacología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Femenino , Regulación de la Expresión Génica , Hepatitis/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Hipoglucemiantes/farmacología , Masculino , Ratones , Ratones Noqueados , Regiones Promotoras Genéticas/genética , Pirimidinas/farmacología , ARN Mensajero/metabolismo , Receptores Tipo I de Interleucina-1/metabolismo , Rosiglitazona , Tiazolidinedionas/farmacología , Transcripción Genética/genética , Activación Transcripcional/genética , Células Tumorales Cultivadas , Regulación hacia Arriba/genéticaRESUMEN
Inflammation and infection have long been known to downregulate the activity and expression of cytochrome P450 (CYP) enzymes involved in hepatic drug clearance. This can result in elevated plasma drug levels and increased adverse effects. Recent information on regulation of human CYP enzymes is presented, as are new developments in our understanding of the mechanisms of regulation. Experiments to study the effects of modulating CYP activities on the inflammatory response have yielded possible insights into the physiological consequences, if not the purpose, of the downregulation. Regulation of hepatic flavin monooxygenases, UDP-glucuronosyltransferases, sulfotransferases, glutathione S-transferases, as well as of hepatic transporters during the inflammatory response, exhibits similarities and differences with regulation of CYPs.
Asunto(s)
Proteínas Portadoras/metabolismo , Regulación Enzimológica de la Expresión Génica/fisiología , Inflamación/metabolismo , Oxigenasas de Función Mixta/metabolismo , Preparaciones Farmacéuticas/metabolismo , Animales , Citocromos/metabolismo , Regulación Enzimológica de la Expresión Génica/genética , Humanos , Inflamación/enzimología , Hígado/metabolismoRESUMEN
Inflammation or infection down-regulates the activity and expression of cytochrome P450 (P450) enzymes involved in hepatic drug clearance, possibly altering drug effectiveness and leading to toxicity. The regulation of UDP-glucuronosyltransferases (UGTs) in inflammation and infection is less well characterized. To determine the response of hepatic and renal UGTs during inflammation and infection, mice were administered either saline or 1 mg/kg lipopolysaccharide (LPS) (16 h), or Citrobacter rodentium by oral gavage (6 days). Hepatic mRNA expression of UGT1A1, 1A9, and 2B5 was similarly down-regulated after LPS exposure and C. rodentium infection, whereas UGT1A2 and 1A6 mRNAs were unchanged. Effects of C. rodentium infection did not require a functional Toll-like receptor 4. Conversely, renal UGT isoforms were relatively unaffected, except for UGT2B5 induction after LPS treatment. Regulation of UGTs during the inflammatory response exhibits similarities to and differences from regulation of P450s, and may be cytokine-mediated.
Asunto(s)
Infecciones por Enterobacteriaceae/enzimología , Glucuronosiltransferasa/biosíntesis , Hepatitis/enzimología , Microsomas/enzimología , Nefritis/enzimología , ARN Mensajero/biosíntesis , Animales , Western Blotting , Citrobacter rodentium/crecimiento & desarrollo , Modelos Animales de Enfermedad , Infecciones por Enterobacteriaceae/microbiología , Infecciones por Escherichia coli/enzimología , Infecciones por Escherichia coli/microbiología , Femenino , Hepatitis/microbiología , Isoenzimas/biosíntesis , Riñón/enzimología , Lipopolisacáridos/administración & dosificación , Hígado/enzimología , Ratones , Ratones Endogámicos , Nefritis/microbiología , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Citrobacter rodentium is the rodent equivalent of human enteropathogenic Escherichia coli infection. This study investigated regulation of hepatic and renal cytochrome P450 (P450) mRNAs, hepatic P450 proteins, cytokines, and acute phase proteins during C. rodentium infection. Female C3H/HeOuJ (HeOu) and C3H/HeJ (HeJ) mice [which lack functional toll-like receptor 4 (TLR4)] were infected with C. rodentium by oral gavage and sacrificed 6 days later. Hepatic CYP4A10 and 4A14 mRNAs were decreased in HeOu mice (<4% of control). CYP3A11, 2C29, 4F14, and 4F15 mRNAs were reduced to 16 to 55% of control levels, whereas CYP2A5, 4F16, and 4F18 mRNAs were induced (180, 190, and 600% of control, respectively). The pattern of P450 regulation in HeJ mice was similar to that in HeOu mice for most P450s, with the exception of the TLR4 dependence of CYP4F15. Hepatic CYP2C, 3A, and 4A proteins in both groups were decreased, whereas CYP2E protein was not. Renal CYP4A10 and 4A14 mRNAs were significantly down-regulated in HeOu mice, whereas other P450s were unaffected. Most renal P450 mRNAs in infected HeJ mice were increased, notably CYP4A10, 4A14, 4F18, 2A5, and 3A13. Hepatic levels of interleukin (IL)-1beta, IL-6, and tumor necrosis factor alpha (TNFalpha) mRNAs were significantly increased in infected HeOu mice, whereas only TNFalpha mRNA was significantly increased in HeJ mice. Hepatic alpha1-acid glycoprotein was induced in both groups, whereas alpha-fibrinogen and angiotensinogen were unchanged. These data indicate that hepatic inflammation induced by C. rodentium infection is mainly TLR4-independent and suggest that hepatic P450 down-regulation in this model may be cytokine-mediated.
Asunto(s)
Sistema Enzimático del Citocromo P-450/genética , Infecciones por Enterobacteriaceae/enzimología , Regulación Enzimológica de la Expresión Génica , Riñón/enzimología , Hígado/enzimología , Receptor Toll-Like 4/genética , Animales , Western Blotting , Citrobacter rodentium/crecimiento & desarrollo , Infecciones por Enterobacteriaceae/genética , Infecciones por Enterobacteriaceae/microbiología , Femenino , Ratones , Ratones Mutantes , Mutación , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Inflammatory agents such as lipopolysaccharide (LPS) down-regulate the hepatic expression of many cytochrome P450 (P450) mRNAs and proteins. Previous studies suggested that suppression of some P450 mRNAs could involve the regulation or modulation of the nuclear receptors peroxisome proliferator-activated receptor alpha (PPARalpha) or pregnane X receptor (PXR). To determine the involvement of these receptors in P450 down-regulation, PPARalpha knockout (KO), PXR KO, and appropriate wild-type (WT) mice were administered either saline or 1 mg/kg LPS. Hepatic mRNA and protein expression of several P450 isoforms, interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF) alpha, alpha1-acid glycoprotein (AGP), and fibrinogen (FBG) were examined 16 h later. LPS administration significantly decreased the hepatic expression of CYP1A2, 2A5, 2C29, 2E1, 3A11, 4A10, and 4A14 mRNAs in both groups of PPARalpha and PXR mice, whereas CYP3A13 mRNA was increased slightly in PPARalpha WT and KO mice, but not in PXR mice. Effects of LPS administration on mouse hepatic P450 proteins (probed using rat P450 2C, 3A, 4A, and 2E antibodies) were consistent with mRNA results in most cases. LPS treatment significantly increased IL-1beta, IL-6, TNFalpha, AGP, and FBG mRNA in both PPARalpha and PXR mice, with the greatest effect observed with TNFalpha. Because decreases in P450 mRNA expression were essentially identical in both WT and KO mice for both nuclear receptors, these data indicate that down-regulation of P450 during inflammation does not require the nuclear receptors PPARalpha and PXR.