Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q8NEX9 (reductase)
 26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inulin enzymatically synthesized from sucrose is a dietary component that completely escapes glucide digestion. Supplementing inulin to a high-fat and high-sucrose diet (HF) ameliorated hypertriglycemia and hepatic steatosis in 8-week-fed rats by suppressing elevated levels of serum triacylglycerols, fatty acids, and glucose, and the accumulation of hepatic triacylglycerols and fatty acids. Inulin intake prevented phenobarbital (PB)- and dexamethasone-induced liver injuries in the HF group. No significant alteration in the baseline expression of CYP2B, CYP2C11, CYP3A, and NADPH-cytochrome P450 (P450) reductase mRNAs and proteins was found. In contrast, baseline and PB-treated expressions of CYP2E1 mRNA were reduced in HF-fed rats. The induction of P450s in response to PB was affected by the nutritional status of the rats; mRNA levels of CYP2B1 and CYP3A1 after PB treatment, as assessed by quantitative real-time polymerase chain reaction analysis were reduced in the inulin-supplemented HF (HF+I) group, compared with those in the HF group. Western blot analysis detected the corresponding changes of CYP2B and CYP3A proteins. These alterations were correlated with changes in hepatic thiobarbituric acid-reactive substances. Furthermore, no significant difference in the expression of nuclear receptors constitutive androstane receptor, pregnane X receptor, and retinoid X receptor alpha and coactivator peroxisome proliferator-activated receptor-gamma coactivator 1alpha proteins was found in the hepatic nucleus between the HF and HF+I groups, but the expression of hepatocyte nuclear factor alpha (HNF4alpha) protein was significantly reduced in the HF+I group. Taken together, these results indicate that inulin intake ameliorates PB-induced liver injury, associated with a decline in lipid accumulation and PB-induced expression of CYP2B and CYP3A, which may be related by a reduction in the nuclear expression of HNF4alpha.
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PMID:Dietary inulin alleviates hepatic steatosis and xenobiotics-induced liver injury in rats fed a high-fat and high-sucrose diet: association with the suppression of hepatic cytochrome P450 and hepatocyte nuclear factor 4alpha expression. 1681 62

To test the hypothesis that supra-elevated hepatic alpha-tocopherol concentrations would up-regulate mechanisms that result in increased hepatic alpha-tocopherol metabolism and excretion, rats received daily subcutaneous alpha-tocopherol injections (10 mg/100 g body wt) and then were sacrificed on Day 0 or 12 h following their previous injection on Days 3, 6, 9, 12, 15, and 18. Liver alpha-tocopherol concentrations increased from 12 +/- 1 nmol/g (mean +/- SE) to 819 +/- 74 (Day 3), decreased at Day 9 (486 +/- 67), and continued to decrease through Day 18 (338 +/- 37). alpha-Tocopherol metabolites and their intermediates increased and decreased similarly to alpha-tocopherol albeit at lower concentrations. There were no changes in known vitamin E regulatory proteins, i.e., hepatic alpha-tocopherol transfer protein or cytochrome P450 (CYP) 4F. In contrast, both CYP3A and CYP2B, key xenobiotic metabolizing enzymes, doubled by Day 6 and remained elevated, while P450 reductase increased more slowly. Consistent with the decrease in liver alpha-tocopherol concentrations, a protein involved in biliary xenobiotic excretion, p-glycoprotein, increased at Day 9, doubling by Day 15. Thus hepatic alpha-tocopherol concentrations altered hepatic proteins involved in metabolism and disposition of xenobiotic agents.
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PMID:Alpha-tocopherol regulation of hepatic cytochrome P450s and ABC transporters in rats. 1696 32

The aim of the present study was to investigate the interaction of 2,4,6-trinitrotoluene (TNT) with liver biotransformation enzymes in European eel Anguilla anguilla (Linnaeus, 1758). Eels were exposed to 0.5, 1 and 2.5mg/l nominal concentrations of TNT for 6 and 24h. Modulation of CYP1A1, UDPGT and GST genes was investigated by real-time PCR. Total CYP450 content, NADPH cytochrome c reductase activity, CYP1A and CYP2B-like activities, such as EROD, MROD and BROD, as well as GST and UDPGT activities, were measured by biochemical assays. An in vitro study was performed on EROD in order to evaluate catalytic modulation by TNT. No modulation of the CYP1A1 gene or protein was observed in TNT-exposed eels. On the other hand, a significant decline of EROD and MROD activities was observed in vivo. An increase in NADPH cyt c reductase, and phase II enzymes (UDPGT and GST) were observed at both gene expression and activity levels. The overall results indicated that TNT is a potential competitive inhibitor of CYP1A activities. A TNT metabolic pathway involving NADPH cyt c reductase and phase II enzymes is also suggested.
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PMID:Interactions of 2,4,6-trinitrotoluene (TNT) with xenobiotic biotransformation system in European eel Anguilla anguilla (Linnaeus, 1758). 1840 54

Preclinical and clinical studies of CYP gene-directed enzyme prodrug therapy have been focused on anticancer prodrugs activated by CYP2B enzymes, which have low endogenous expression in human liver; however, the gene therapeutic potential of CYP3A enzymes, which are highly expressed in human liver, remains unknown. This study investigated methoxymorpholinyl doxorubicin (MMDX; nemorubicin), a novel CYP3A-activated anticancer prodrug. Retroviral transfer of CYP3A4 increased 9L gliosarcoma cell chemosensitivity to MMDX 120-fold (IC(50)=0.2 nM in 9L/3A4 cells). In CHO cells, overexpression of P450 reductase in combination with CYP3A4 enhanced chemosensitivity to MMDX, and to ifosfamide, another CYP3A4 prodrug, 11- to 23-fold compared with CYP3A4 expression alone. CYP3A4 expression and MMDX chemosensitivity were increased in human lung (A549) and brain (U251) tumor cells infected with replication-defective adenovirus encoding CYP3A4. Coinfection with Onyx-017, a replication-conditional adenovirus that coamplifies and coreplicates the Adeno-3A4 virus, led to large increases in CYP3A4 RNA but only modest increases in CYP3A4 protein and activity. MMDX induced remarkable growth delay of 9L/3A4 tumors, but not the P450-deficient parental 9L tumors, in immunodeficient mice administered low-dose MMDX either intravenous or by direct intratumoral (i.t.) injection (60 microg kg(-1), every 7 days x 3). Notably, the i.t. route was substantially less toxic to the mouse host. No antitumor activity was observed with intraperitoneal MMDX treatment, suggesting a substantial hepatic first pass effect, with activated MMDX metabolites formed in the liver having poor access to the tumor site. These studies demonstrate that human CYP3A4 has strong potential for MMDX prodrug-activation therapy and suggest that endogenous tumor cell expression of CYP3A4, and not hepatic CYP3A4 activity, is a key determinant of responsiveness to MMDX therapy in cancer patients in vivo.
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PMID:Potentiation of methoxymorpholinyl doxorubicin antitumor activity by P450 3A4 gene transfer. 1901 99

To determine the in vivo function of intestinal cytochrome P450 (P450) enzymes, we have generated an intestinal epithelium (IE)-specific P450 reductase gene (Cpr) knockout mouse model (designated IE-Cpr-null). In the IE-Cpr-null mouse, CPR expression was abolished in IE cells; however, CPR expression was not altered in other tissues examined. The loss of CPR expression in the small intestine (SI) led to increased expression of several P450 proteins examined, including CYP1A1, CYP2B, CYP2C, and CYP3A. It is interesting to note that the expression of CYP1A1 was also increased in the liver, kidney, and lung of the IE-Cpr-null mice compared with wild-type (WT) littermates, a result strongly supporting the notion that SI metabolism of putative dietary CYP1A1 inducers can influence the systemic bioavailability of these inducers. The rates of SI microsomal metabolism of nifedipine (NFP) in the IE-Cpr-null mice were approximately 10% of the rates in WT littermates, despite the compensatory expression of multiple P450 enzymes in the SI. Furthermore, the area under the concentration-time curve (AUC) values for blood NFP (dosed at 10 mg/kg) levels were 1.6-fold higher in IE-Cpr-null mice than in WT littermates when NFP was given orally; in contrast, the AUC values were comparable for the two strains when NFP was given intravenously. This result directly showed that P450-catalyzed NFP metabolism in the SI plays an important role in the first-pass clearance of oral NFP. Our findings indicate that the IE-Cpr-null mouse model can be used to study the in vivo function of intestinal P450 enzymes in the clearance of oral drugs and other xenobiotics.
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PMID:An intestinal epithelium-specific cytochrome P450 (P450) reductase-knockout mouse model: direct evidence for a role of intestinal p450s in first-pass clearance of oral nifedipine. 1905 12

The study was originally designed to test the hypothesis that the compensatory increase in intestinal P450 (cytochrome P450) expression in the intestinal epithelium-specific P450 reductase (CPR) knockout (IE-Cpr-null) mice was attributable to decreased metabolism of putative P450 inducers present in the diet. Thus, we determined the impact of a dietary change from regular rodent chow to a synthetic diet devoid of phytochemicals on the expression of P450 enzymes in the small intestine (SI) and liver of wild-type (WT) and IE-Cpr-null mice. The dietary change diminished expression of CYP1A, 2B, 2C, and 3A in SI and CYP2B, 2C, and 3A in liver of both WT and IE-Cpr-null mice. However, the compensatory increase in SI P450 expression still occurred in IE-Cpr-null, compared with WT, mice, on the synthetic diet. The diet change-induced decrease in P450 expression was accompanied by decreases in microsomal midazolam-hydroxylase activity in vitro and first-pass clearance of midazolam in vivo in WT mice. Further studies showed that the dietary change, but not Cpr deletion, caused large decreases in bile acid (BA) levels in plasma, liver, SI, and intestinal content and that treatment of WT mice on the synthetic diet with GW4064, a farnesoid-X-receptor agonist, restored the levels of CYP3A expression in both liver and SI to those seen in mice fed with regular chow. Taken together, these results highlight the vital role of diet in maintaining adequate expression of major drug-metabolizing P450s and their associated drug-metabolizing activities in the digestive tract and suggest potential involvement of BA signaling in the regulatory mechanisms.
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PMID:Dietary regulation of mouse intestinal P450 expression and drug metabolism. 2316 Aug 19

Tissue-specific deletion of the gene for NADPH-cytochrome P450 (P450) reductase (CPR), the essential electron donor to all microsomal P450 enzymes, in either liver or intestine, leads to upregulation of many P450 genes in the tissue with the Cpr deletion. Here, by studying the liver-specific Cpr-null (LCN) mouse, we examined whether an interorgan regulatory pathway exists, such that a loss of hepatic CPR would cause compensatory changes in intestinal P450 expression and capacity for first-pass metabolism of oral drugs. We show for the first time that intestinal expression of CYP2B, 2C, and 3A proteins was increased in LCN mice by 2- to 3-fold compared with wild-type (WT) mice, accompanied by significant increases in small intestinal microsomal lovastatin-hydroxylase activity and systemic clearance of oral lovastatin (at 5 mg/kg). Additional studies showed that the hepatic Cpr deletion, which caused large decreases in bile acid (BA) levels in the liver, intestine, plasma, and intestinal content, led to drastic decreases in the mRNA levels of intestinal fibroblast growth factor 15 (FGF15), a target gene of the BA receptor farnesoid X receptor. Furthermore, treatment of mice with FGF19 (the human counterpart of mouse FGF15) abolished the difference between WT and LCN mice in small intestinal (SI) CYP3A levels at 6 hours after the treatment. Our findings reveal a previously unrecognized direct role of intestinal FGF15/19 in the regulation of SI P450 expression and may have profound implications for the prediction of drug exposure in patients with compromised hepatic P450 function.
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PMID:Regulation of intestinal cytochrome P450 expression by hepatic cytochrome P450: possible involvement of fibroblast growth factor 15 and impact on systemic drug exposure. 2418 63


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