Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serum of rabbits with a turpentine-induced acute inflammatory reaction (RS(INFLA)) and serum of humans with a viral infection (HS(INF)) were previously shown to diminish hepatic cytochrome P450 (P450) content and activity. To document the role of reactive oxygen intermediates in the serum-mediated decrease in P450 content and activity, hepatocytes of rabbits with an acute inflammatory reaction (H(INFLA)) were incubated with RS(INFLA) and HS(INF) for 4 h, and total P450 content (spectrally measurable P450), P450 activity (assessed by estimating the formation of theophylline metabolites), and amount of CYP1A1, CYP1A2, and CYP3A6 proteins were measured. RS(INFLA) or HS(INF) decreased P450 content and activity without affecting the amount of CYP1A1 and -1A2 H(INFLA). Exposure of H(CONT) or H(INFLA) to hydrogen peroxide (0.01-1.0 mM) and sodium nitroprusside (0.01-1.0 mM) produced a dose-dependent decrease in P450 content and in the formation of theophylline metabolites without modifying the amount of CYP1A1 and CYP1A2, whereas lipid peroxidation increased. Incubation of L-NAME (0.05-1.0 mM), dimethylthiourea (6.25-50 mM), or N-acetylcysteine (0.01-1.0 mM) with H(INFLA) partially prevented the decrease in P450 content and activity and the increased lipid peroxidation induced by RS(INFLA) and HS(INF). On the other hand, 3-amino-1,2,4-triazole (10-100 mM) or diethyldithiocarbamate (1.0-10 mM) potentiated RS(INFLA)- and HS(INF)-mediated decreases in P450 content and activity and the increase in lipid peroxidation, without affecting the amount of CYP1A1 or -1A2; DL-buthionine-(S,R)-sulfoximine (2.5-25 mM) potentiated only the inhibition of 1,3-dimethyluric acid formation. It is concluded that reactive oxygen intermediates are implicated in the decrease of H(INFLA) P450 content and activity induced by 4 h of exposure to RS(INFLA) or HS(INF).
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PMID:Role of reactive oxygen intermediates in the decrease of hepatic cytochrome P450 activity by serum of humans and rabbits with an acute inflammatory reaction. 1095 Aug 58

A turpentine-induced inflammatory reaction (TIIR) down-regulates multiple isoforms of hepatic cytochrome P450 (P450) and increases microsomal lipid peroxidation. Since the synthesis of nitric oxide (NO*) is stimulated by inflammatory reactions, and NO* can depress the P450, it was of interest to investigate in vivo whether L-NAME and theophylline, by its anti-inflammatory properties, could prevent the depression of P450 caused by a TIIR. Control and rabbits with a TIIR received L-NAME for 72 h, and the activity of P450 was assessed in vivo and in vitro. In vivo, TIIR reduced theophylline systemic clearance by 50% (p<0.05), P450 total content by 67%, and the amount of CYP1A1/2 proteins by around 60% (p<0.05). L-NAME partially prevented the decrease in theophylline systemic clearance and in P450 total content, as well as the increase in lipid peroxidation; however, L-NAME did not hinder CYP1A1/2 proteins down-regulation. L-NAME did not modify the in vitro ability of the serum of rabbits with TIIR to decrease P450 activity, suggesting that the effect of L-NAME is not associated to a decrease in serum mediators. As assessed by the concentration in seromucoids, theophylline did not modify the severity of the inflammatory reaction, nor did it prevent the decrease in P450 activity. In conclusion, a TIIR down-regulates and reduces P450 activity, decrease that is at least in part mediated by NO*; theophylline does not prevent TIIR-induced P450 decrease in activity.
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PMID:L-NAME prevents in vivo the inactivation but not the down-regulation of hepatic cytochrome P450 caused by an acute inflammatory reaction. 1155 17

Many xenobiotics are metabolized and detoxified by cytochrome P-450s (CYP). The xenobiotics metabolizing CYPs are induced by various kinds of receptors. To induce CYP1A1, the Ah receptor requires a ligand for its activation as a transcription factor. On the other hand, benzimidazole compounds can induce CYP1A1 without binding to the Ah receptor as a ligand (ligand-independent pathway). In response to phenobarbital (PB) and other PB-type inducers, the nuclear receptor CAR (the NR-constitutive active receptor) translocates to the nucleus, forms a dimer with the retinoid X receptor (RXR), and activates the PB-responsive enhancer module (PBREM) in the PB-inducible CYP2B genes. For human CYP3A4 genes, pregnane X receptor (PXR) binds to the xenobiotic-responsive enhancer module (XREM) and upon induction by rifampicin, a PXR:RXR heterodimer could transactivate XREM.
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PMID:[Regulation of cytochrome P-450 (CYP) genes by nuclear receptors]. 1186 91

In contrast to the well-known Ah receptor-mediated regulation of the CYP1A1 gene by polycyclic aromatic hydrocarbons, the molecular mechanism by which phenobarbital (PB) and PB-like inducers affect transcription of CYP genes remains unknown; no receptor for these chemicals has been found to date. However, in the last 5 years PB-responsive sequences have been identified in the 5' flanking regions of several P450 genes. The phenobarbital-responsive enhancer unit (PBRU) of CYP2B gene family members contain two potential nuclear receptor binding sites (NR1 and NR2) that flank a nuclear factor 1 (NF-1) binding motif. The nuclear factors that regulate PBRU activity have not yet been characterized. It seems that PB may activate multiple nuclear orphan receptors to induce various CYP genes. CYP2B and CYP3A genes appear to be targets for the orphan receptors CAR and PXR, respectively. It is also possible that the pleiotropic effects of PB can, in part, be explained by the ability of the CAR-RXR heterodimer to bind to a variety of nuclear receptor binding motifs. The induction of cytochromes P450 may result in interactions between xenobiotics and in the interference of xenobiotic metabolism and endogenous signalling pathways.
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PMID:Phenobarbital-induced expression of cytochrome P450 genes. 1199 99

Dimethyl sulfoxide (DMSO) is reported to induce hepatocyte redifferentiation. The impact of DMSO on liver transcription factors, cytochromes P450 (CYPs), and nuclear receptors regulating CYP expression was assayed in primary rat hepatocytes by QPCR. CYP 2B1, 3A1, and 4A1 mRNAs were reduced to 10-30% of initial liver levels without DMSO and restored at or above liver levels by DMSO treatment. In contrast, CYP1A1 mRNA increased approximately 5-fold during the course of culture, independent of DMSO. DMSO enhanced expression of the nuclear receptors CAR, PXR, and PPARalpha 2- to 5-fold, which may contribute to the increase in basal CYP expression. Without DMSO, liver transcription factors were decreased (HNF4, C/EBPalpha), largely unchanged (HNF1alpha, HNF3alpha, and C/EBPbeta) or elevated (HNF3beta, HNF6) compared to intact liver. DMSO largely restored hepatic levels of HNF4 and C/EBPalpha, partially suppressed the elevated levels of HNF6, increased HNF1alpha approximately 2-fold, and had little effect on HNF3alpha, HNF3beta, and C/EBPbeta. Overall, DMSO helped maintain normal hepatic transcription factor patterns and basal CYP and nuclear receptor profiles, suggesting that hepatocytes cultured with DMSO may be useful for CYP metabolic studies under conditions where the endogenous liver phenotype is preserved.
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PMID:Impact of dimethyl sulfoxide on expression of nuclear receptors and drug-inducible cytochromes P450 in primary rat hepatocytes. 1504 95

We found five novel nonsynonymous polymorphisms of the human CYP1A1 gene from Japanese individuals. The five single nucleotide polymorphisms (SNP) in exon 7 (2346_2347 ins T, 2414T>A, 2461C>T, 2500C>T and 2546C>G causing premature stop codon, Ile(448)Asn, Arg(464)Cys, and Arg(477)Trp and Pro(492)Arg, respectively) were as follows:SNP, 030212Saito001; GENE NAME, CYP1A1; ACCESSION NUMBER, X02612; LENGTH, 25 base; 5'-GTCAACCCATCT-/TGAGTTCCTACCT-3'.SNP, 030212Saito002; GENE NAME, CYP1A1; ACCESSION NUMBER, X02612; LENGTH, 25 base; 5'-GTGAGAAGGTGAT/ATATCTTTGGCAT-3'.SNP, 030212Saito003; GENE NAME, CYP1A1; ACCESSION NUMBER, X02612; LENGTH, 25 base; 5'-GAGACCGTTGCCC/TGCTGGGAGGTCT-3'.SNP, 030212Saito004; GENE NAME, CYP1A1; ACCESSION NUMBER, X02612; LENGTH, 25 base; 5'-ATCCTGCTGCAAC/TGGGTGGAATTCA-3'.SNP, 030212Saito005; GENE NAME, CYP1A1; ACCESSION NUMBER, X02612; LENGTH, 25 base; 5'-TGGACATGACCCC/GCATCTATGGGCT-3'.
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PMID:Novel nonsynonymous polymorphisms of the CYP1A1 gene in Japanese. 1561 38

In addition to its natural presence at high concentrations in some areas, uranium has several civilian and military applications that could cause contamination of human populations, mainly through chronic ingestion. Reports describe the accumulation of this radionuclide in some organs (including the bone, kidney, and liver) after acute or chronic contamination and show that it produces chemical or radiological toxicity or both. The literature is essentially devoid of information about uranium-related cellular and molecular effects on metabolic functions such as xenobiotic detoxification. The present study thus evaluated rats chronically exposed to depleted uranium in their drinking water (1mg/(ratday)) for 9 months. Our specific aim was to evaluate the hepatic and extrahepatic mRNA expression of CYP3A1/A2, CYP2B1, and CYP1A1 as well as of the nuclear receptors PXR, CAR, and RXR in these rats. CYP3A1 mRNA expression was significantly higher in the brain (200%), liver (300%), and kidneys (900%) of exposed rats compared with control rats, while CYP3A2 mRNA levels were higher in the lungs (300%) and liver (200%), and CYP2B1 mRNA expression in the kidneys (300%). Expression of CYP1A1 mRNA did not change significantly during this study. PXR mRNA levels increased in the brain (200%), liver (150%), and kidneys (200%). Uranium caused CAR mRNA expression in the lungs to double. Expression of RXR mRNA did not change significantly in the course of this study, nor did the hepatic activity of CYP2C, CYP3A, CYP2A, or CYP2B. Uranium probably affects the expression of drug-metabolizing CYP enzymes through the PXR and CAR nuclear receptors. These results suggest that the stimulating effect of uranium on these enzymes might lead to hepatic or extrahepatic toxicity (or both) during drug treatment and then affect the entire organism.
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PMID:In vivo effects of chronic contamination with depleted uranium on CYP3A and associated nuclear receptors PXR and CAR in the rat. 1603 71

Polybrominated diphenyl ethers (PBDEs), used as flame retardants, have been detected in the environment and in mammalian tissues and fluids. Evidence indicates that PBDE mixtures induce CYPs through aryl hydrocarbon receptor (AhR)-dependent and -independent pathways. The present work has investigated the effects of individual components of a commercial PBDE mixture (DE71) on expression of CYP1A1, a biomarker for activation of the AhR (dioxin-like), and CYP2B and CYP3A, biomarkers for activation of the constitutive androstane and pregnanexreceptors (CAR and PXR), respectively, in the rat. Male F344 rats were dosed orally on three consecutive days with either DE71, PBDE components, 2,2',4,4'-tetraBDE (BDE47), 2,2',4,4',5-pentaBDE (BDE99), 2,2',4,4',5,5'-hexaBDE (BDE153), representative polybrominated dibenzofurans (PBDFs) present in DE71, or reference PCBs. Differential expression of target genes was determined in liver 24 h after the last dose. Quantitative PCR analysis indicated up-regulation of CYP1A1 by DE71; however, the response was weak compared to that for dioxin-like PCB126. Individual PBDE components of DE71 up-regulated CYP1A1 only at the highest administered dose (100 micromol/kg/day). Representative PBDFs efficiently up-regulated CYP1A1; therefore, they, along with other PBDFs and polybrominated dibenzodioxins detected in DE71 and individual PBDE components, may be responsible for most, if not all, dioxin-like properties previously observed for PBDEs. Conversely, PBDEs appear capable of up-regulating CYP2B and CYP3A in rats at doses similar to that for non-dioxin-like PCB153. These results indicate that in vivo PBDE-mediated toxicity would be better categorized by AhR-independent mechanisms, rather than the well-characterized AhR-dependent mechanism associated with exposure to dioxin-like chemicals.
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PMID:Differential expression of CYP1A, 2B, and 3A genes in the F344 rat following exposure to a polybrominated diphenyl ether mixture or individual components. 1610 49

The brominated flame retardants tetrabromobisphenol A (TBBPA) and hexabromocyclododecane (HBCD) are found in the environment, e.g., in sediments and organisms, in food items, human blood samples and mother's milk. In this study, the effects of both compounds on rat hepatic cytochrome P450 (CYP) levels and activities were investigated. Juvenile/young male and female Wistar rats were treated orally with various doses via the feed (TBBPA) or by gavage (HBCD). After 28 days of treatment the animals were sacrificed and hepatic mRNA and microsomes were isolated. HBCD treatment led to a significant induction of CYP2B1 mRNA, CYP2B1/2B2 protein and 7-pentoxyresorufin O-depentylase (PROD) activity suggesting a phenobarbital-type of induction. Furthermore, a significant increase in CYP3A1/3A3 mRNA, CYP3A1 protein, and luciferin benzylether debenzylase (LBD) activity was found, being more pronounced in females than in males. The effect on CYP3A1/3A3 mRNA was significant in female rats at a daily dose of 3.0mg/kg body weight and above. HBCD exhibited no effects on CYP1A2 mRNA, CYP1A1/1A2 protein, or microsomal 7-ethoxyresorufin O-deethylase (EROD) activity suggesting lack of activation of the aryl hydrocarbon receptor. No significant effects on any of the parameters measured were obtained with TBBPA. Our findings suggest that oral exposure to HBCD induces drug-metabolising enzymes in rats probably via the CAR/PXR signalling pathway. Induction of CYPs and co-regulated enzymes of phase II of drug metabolism may affect homeostasis of endogenous substrates including steroid and thyroid hormones.
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PMID:Subacute effects of the brominated flame retardants hexabromocyclododecane and tetrabromobisphenol A on hepatic cytochrome P450 levels in rats. 1632 80

Nitric oxide (NO) plays an important role in the pathophysiology of sepsis and septic shock but the mechanism is not well understood. The aim of this study was to investigate the role of NO in the cytochrome P450 (CYP) isozyme activity and the expression of its gene during polymicrobial sepsis. The rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). Aminoguanidine (AG, 100 mg/kg body weight) or N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 mg/kg body weight) was injected intraperitoneally at 0, 3, 6, 10, and 20 h after CLP. The plasma nitrite/nitrate concentration increased 24 h after CLP, and this increase was almost completely abolished by AG and L-NAME. Sepsis increased the serum aminotransferase and lipid peroxidation levels, which were attenuated by AG but augmented by L-NAME. The hepatic concentration of the reduced gluthathione decreased in the CLP rats, which was inhibited by AG but augmented by L-NAME. The total CYP content decreased after CLP, which was restored by AG and L-NAME. The CYP1A1, 1A2, and 2E1 activities, along with their protein levels, decreased 24 h after CLP but these decreases were reversed by AG and L-NAME. The CYP1A1, 1A2, 2B1, and 2E1 mRNA expression levels decreased 24 h after CLP, and L-NAME inhibited this decrease. NO plays a key role in the sepsis-mediated decrease in CYP via the interplay of two different mechanisms: NO-dependent suppression of protein via the enhanced inducible NO synthase, and NO-dependent transcriptional suppression via endothelial NO synthase.
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PMID:Role of nitric oxide in the inhibition of liver cytochrome P450 during sepsis. 1688 34


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