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)

Because a number of studies suggest that the developmental expression of cytochrome P-450s (CYP) in Clara cells is species specific, this study was designed to compare the developmental patterns of the isoform CYP2B and NADPH reductase protein expression and CYP2B activity with the time course of smooth endoplasmic reticulum (SER) formation in Clara cells of rat lung. Pulmonary CYP2B activity measured as pentoxyresorufin O-dealkylation in lung homogenates was not detectable before 7 days postnatal age, but was detectable at adult levels at 50 days postnatal age. In Clara cells, CYP2B and NADPH reductase were detected immunohistochemically at 4 days postnatal age and at adult levels at 10 days postnatal age. The volume density of SER in Clara cells of terminal bronchioles measured morphometrically increased significantly with postnatal age. We conclude that in the rat 1) CYP2B and NADPH reductase distribution and CYP2B activity are age dependent; 2) the increase in Clara cell SER precedes the expression of CYP2B protein; 3) cellular appearance of CYP2B protein precedes CYP activity; and 4) SER appearance and P-450 protein expression do not occur uniformly in differentiating Clara cells, even within the same bronchiole.
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PMID:Pulmonary cytochrome P-450 monooxygenase system and Clara cell differentiation in rats. 757 74

A metallothionein-I-transgenic mouse strain (MT-TG) was characterized to determine whether they would be suitable to study the functions of this protein. MT-TG mice were visually indistinguishable from nontransgenic littermate controls, but had 10- to 20-fold higher basal levels of MT protein in pancreas, liver, and stomach, as well as 2- to 6-fold higher MT protein levels in other organs (kidney, intestine, uterus, testes, spleen, heart, and lung) than control mice, as determined by the Cd/hemoglobin assay. The MT-TG mice had 50% more Zn in liver and 300% more Zn in pancreas than control mice. Interestingly, female MT-TG mice have 4- to 5-fold higher MT levels in liver than those of males. To determine whether MT can be further increased by well-known MT inducers, control and MT-TG mice were given Zn (200 mumol/kg), Cd (20 mumol/kg), or diethyl maleate (DEM, 5 mmol/kg), and tissue MT concentrations were measured 24 hr later. MT-TG mice responded to MT inducers in a manner similar to control mice. The hepatic antioxidant components (glutathione (GSH), GSH-peroxidase, GSH-reductase, GSH S-transferase, superoxide dismutase, DT-diaphorase, and catalase) of MT-TG mice were not different from those of controls. The cytochrome P450 enzymes (total P450, b5, NADPH cytochrome c reductase) were normal in these MT-TG mice. The activities of CYP1A, CYP2B, and CYP2E enzymes in MT-TG mice were also similar to those of controls, as determined by ethoxy- and pentoxyresorufin O-dealkylation and chlorzoxazone 6-hydroxylation. Thus, MT-TG mice appear to be a good model for studying functions of MT.
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PMID:Characterization of metallothionein-I-transgenic mice. 764 27

The role of cytochrome P450 (CYP) in the one-electron reductive bioactivation of Adriamycin (ADR) (doxorubicin) was investigated in subcellular fractions of the rat liver. The rate of one-electron reduction of ADR to its semiquinone free radical (ADRSQ), measured by ESR, was 5-fold greater with phenobarbital (PB)-induced (PB microsomes) than with beta-naphthoflavone (beta NF)-induced (beta NF microsomes) rat liver microsomes under anaerobic conditions. ADRSQ formation was inhibited by SK&F 525-A and metyrapone (MP) in PB microsomes but was not significantly inhibited in beta NF microsomes. Under aerobic conditions, the formation of ADRSQ from ADR was diminished in microsomal incubations and concomitant reduction of molecular oxygen occurred instead. Whereas ADR-induced H2O2 formation in PB microsomes was strongly inhibited by SK&F 525-A and MP, only a slight inhibition was observed with 2-ethylnylnaphthalene and 1-ethynylpyrene in beta NF microsomes. In addition, MP produced strong inhibition of ADR-stimulated lipid peroxidation in PB microsomes, compared with beta NF microsomes. The idea that CYP2B1 was involved in the one-electron reduction of ADR in PB microsomes and in reconstituted systems of purified CYP2B1 and purified NADPH-CYP reductase (RED) under anaerobic conditions could be concluded from inhibition studies using SK&F 525-A and antibodies (KO1) against CYP2B enzymes. Moreover, it was calculated from reconstitution experiments using varying amounts of purified CYP2B1 and purified RED that the contribution of CYP2B1 to the one-electron reduction of ADR was similar to that of RED alone.
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PMID:Cytochrome P450 2B1-mediated one-electron reduction of adriamycin: a study with rat liver microsomes and purified enzymes. 826 64

Previously, we showed that the pretreatment of dichloroacetic acid (DCA) increased CHCl3-induced hepatotoxicity in vivo and CHCl3 metabolism in vitro in both male and female rats. The effects of DCA on hepatic cytochrome P450-dependent monooxygenases were studied in this experiment. Male and female Sprague-Dawley rats were treated with DCA (each 2.45 mmol/kg) three times (9 AM, 4 PM, and 9 AM) and hepatic microsomes were prepared 3 hr after the last treatment (the same procedure as previous studies). After DCA treatment, the total content of cytochrome P450 (0.67 nmol/mg protein vs 0.79) and the activity of NADPH-dependent cytochrome P450 reductase (227 nmol/mg protein/min vs 332) were significantly increased in female rats, but they were unchanged in males (0.99 vs 0.98 for P450; 315 vs 311 for reductase). Induction of CYP2E1 was observed in both sexes, evidenced as increased activities of aniline and p-nitrophenol hydroxylases and increased CYP2E1 protein amount determined by immunoblot assay. In contrast, the CYP2B-related activity (dealkylation of pentoxyresorufin) and immunoreactive protein did not increase after DCA treatment in either males or females. The activity of ethoxyresorufin dealkylase was decreased in DCA-treated males compared to their controls (310 pmol/mg protein/min vs 229, p < 0.05), but it was not significantly affected in females. These data demonstrate that DCA treatment of both male and female rats altered the population of hepatic cytochrome P450. The results support the hypothesis that DCA increases CHCl3 metabolism, and therefore hepatotoxicity, by inducing CYP2E1.
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PMID:Dichloroacetic acid treatment increases hepatic CYP2E1 in male and female rats. 897 62

Human CYP3A, the most abundant hepatic and intestinal cytochrome P450, catalyzes the metabolism of a diverse array of xenobiotics. Dimethyl sulfoxide is a commonly used solvent which has been used therapeutically. Dimethyl sulfoxide effects on CYP3A, CYP2E1, CYP2B and NADPH cytochrome P450 reductase expression in rat liver and in primary cultured rat hepatocytes were examined. Dimethyl sulfoxide increased immunodetectable hepatic CYP3A and CYP2E1 levels approximately 2.5 to 3-fold in the absence of any change in the respective mRNA levels. No change in CYP2B or P450 reductase expression was observed, indicating that dimethyl sulfoxide effects were selective. Dimethyl sulfoxide also increased CYP3A protein in rats pretreated with dexamethasone. In primary cultured rat hepatocytes, dimethyl sulfoxide increased CYP3A and CYP2E1 protein without increasing the respective mRNA levels. These results show that dimethyl sulfoxide, at levels relevant to human exposure, enhances CYP3A and CYP2E1 expression by posttranscriptional mechanisms.
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PMID:Posttranscriptional elevation of cytochrome P450 3A expression. 907 Feb 49

3,3',4,4'-Tetrachlorobiphenyl (TCB) can induce and inhibit cytochrome P450 1A1 (CYP1A1) in vertebrates. TCB may also suppress CYP1A1 protein levels, but the mechanism is unknown. This study examined transcriptional and translational aspects of hepatic CYP1A1 regulation in the fish scup (Stenotomus chrysops) given single intraperitoneal injections of low (0.1 mg/kg) or high (5 mg/kg) doses of TCB, and sampled over 16 days. The low dose strongly induced hepatic CYP1A1 mRNA (25-fold), protein (12-fold), and activity [ethoxyresorufin O-deethylase (EROD)] (15-fold). The high dose also strongly induced CYP1A1 mRNA (29-fold), in a pattern like that at the low dose, but microsomal CYP1A1 protein content was induced only 4-fold and EROD rates were near control levels. Both TCB doses caused similar increases in microsomal cytochrome b5 content, and in rates of NADPH-cytochrome c (P450) reductase and UDP-glucuronosyltransferase (with p-nitrophenol). The contents of CYP forms other than CYP1A1 (putative CYP2B or CYP3A) were only weakly affected by TCB at either dose. The strong and largely specific post-transcriptional suppression of CYP1A1 content was associated with high concentrations of TCB measured in the liver. Incubation of scup hepatic microsomes with TCB plus NADPH led to a time-dependent inactivation of CYP1A1 that was distinct from catalytic inhibition, and appeared not to involve reactive metabolites of TCB. This in vitro result suggests that TCB may inactivate CYP1A1 in vivo, which could account for the apparent antagonistic effect of TCB on CYP1A1 induction.
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PMID:Induction and post-transcriptional suppression of hepatic cytochrome P450 1A1 by 3,3',4,4'-tetrachlorobiphenyl. 917 17

Various studies indicate that cytodifferentiation of Clara cells and development of pulmonary cytochrome P450 (CYP) monooxygenases occur postnatally. The timing of these events is species-specific. Neonatal mice are more susceptible than adult mice are to Clara cell injury by naphthalene, but little is known about the postnatal development of Clara cells and CYP in mice. This study was designed to determine the developmental pattern of Clara cell differentiation and CYP expression in mice. Lungs from mice aged 16 days gestation to 63 days postnatal (DPN) were studied. Clara cell secretory protein (CC10) expression in nonciliated cells was detected earlier in proximal airways than in distal airways, but reached adult levels at 14 DPN in all airway levels. Cilia-associated tubulin expression closely followed the onset of CC10 expression, as did expression of CYP reductase. CYP2B protein expression appeared and differentiated earlier in bronchi than in bronchioles and reached adult levels at 14 and 28 DPN, respectively. CYP2F2 expression appeared earlier in proximal airways, but did not reach adult levels of expression until after 28 DPN. CYP activity, measured by naphthalene metabolism, increased with age and corresponded to CYP2F2 protein expression. We conclude that in the mouse, (1) Clara cell maturation is a postnatal event, (2) Clara cell differentiation is complete at the same age in proximal and distal airways, (3) CYP reductase protein expression occurs at the same time as CC10 expression, but CYP2B and CYP2F2 lag behind, and (4) stereoselective naphthalene monooxygenase activity corresponds with CYP2F2 protein expression.
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PMID:Pulmonary cytochrome P450 monooxygenase and Clara cell differentiation in mice. 930 17

The distribution of pulmonary cytochrome P450 (P450 or CYP) isoforms has been investigated primarily in immunohistochemical studies, which are neither quantitative nor reflective of the functions of these enzymes. Studies of enzyme activities have been performed using whole-lung homogenates or isolated cells, but there is little information on the regioselective expression of P450 monooxygenases. The aims of this study were to compare the activities of P450 monooxygenases in different lung subcompartments in two commonly studied animal models, i.e. rats and monkeys, and to explore the possibility that inducing agents would result in activity up-regulation that is highly site-selective, using rats as a model. Microdissection techniques were used to separate the airways from blood vessels and lung parenchyma. In rats, CYP1A1 (ethoxyresorufin) and CYP2B (pentoxyresorufin) dealkylase activities were highest in the parenchyma, whereas CYP2E1 (p-nitrophenol) hydroxylase activity was highest in the airways. P450 reductase activities were similar in airways and parenchyma and were lower in trachea. In monkeys, no significant site-selective differences in CYP1A1 and CYP2B1 activities were found. In contrast, CYP2E1 activity was higher in the distal bronchioles and parenchyma than in the proximal airways. P450 reductase activities were similar in microsomes prepared from all subcompartments of monkey lung. Induction of rat CYP1A1 activity by beta-naphthoflavone (administered ip) was much greater in the airways and lung parenchyma ( approximately 30-fold) than in the liver ( approximately 10-fold) or trachea ( approximately 2.5-fold). Oral administration of phenobarbital or acetone increased CYP2B and CYP2E1 activities in rat liver but had no significant effect on P450 activities in subcompartments of rat lung. These findings support the conclusion that there are regiospecific and species-specific differences in the activities of P450 isoforms and that the inducibility of rat pulmonary P450s is dependent on the isoform and lung region.
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PMID:Site-selective differences in cytochrome P450 isoform activities. Comparison of expression in rat and rhesus monkey lung and induction in rats. 957 Dec 20

The in vitro metabolism of [14C]-nonylphenols (NPs) by rat hepatic microsomes in vitro was examined. Product formation was NADPH dependent and inhibited by the cytochrome P450 inhibitors, piperonyl butoxide and SKF525. Hepatic microsomes isolated from various inducer-treated rats (including beta naphthoflavone, phenobarbital, ethanol, dexamethasone, and clofibrate which selectively induce CYP1A, 2B, 2E, 3A and 4A, respectively) all metabolized NPs. Only microsomes from phenobarbital-treated rats exhibited a significantly higher activity towards NPs and showed a different profile of NP metabolites compared to control, untreated rats. Microsomes from human CYP2B6 transfected cells with endogenous NADPH-P450 reductase activity but not microsomes from the non-transfected parent cells metabolized NPs. The metabolism of NPs using microsomes from phenobarbital-treated rats was inhibited by 4-amino-2, 6-dinitro-1-t-butylxylene, a specific CYP2B enzyme inhibitor. Addition of a general anti-CYP2B sera to the reaction mixture attenuated the enzyme activity of microsomes from phenobarbital-treated rats to metabolize NPs. This metabolic reaction was, however, insensitive to a specific anti-CYP2B1 sera that had been shown to inhibit enzyme activities attributed only to CYP2BI suggesting that the CYP2B2 pathway is predominant in NP metabolism. The results indicate that hepatic cytochrome P450 enzyme(s) can metabolize NPs and that CYP2B isozymes are probably involved.
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PMID:Metabolism of nonylphenol by rat and human microsomes. 981 83

Administration of the antineoplastic doxorubicin to rodents causes depression of hepatic cytochrome P450 (CYP) dependent biotransformation, an effect that has been partially attributed to the ability of doxorubicin to stimulate microsomal lipid peroxidation. Since doxorubicin can be bioactivated by the CYP/NADPH-CYP reductase system to products that bind covalently to microsomal protein, we hypothesized that doxorubicin functions as a mechanism-based inactivator of hepatic microsomal CYPs and (or) NADPH-CYP reductase under conditions in which doxorubicin-stimulated NADPH-dependent lipid peroxidation is minimized. In vitro studies were conducted with hepatic microsomes isolated from untreated and phenobarbital-treated male rats. Unlike the positive control carbon tetrachloride, doxorubicin (10 microM) did not stimulate NADPH-dependent lipid peroxidation in microsomal incubations containing EDTA (1.5 mM). Doxorubicin did not cause NADPH-dependent loss of microsomal CYP, heme, or steroid hydroxylation activities selective for CYP2A, CYP2B, CYP2C11, and CYP3A. The positive control 1-aminobenzotriazole caused marked NADPH-dependent decreases in all of these parameters. Neither doxorubicin nor 1-aminobenzotriazole caused NADPH-dependent loss of NADPH-CYP reductase activity, and neither compound altered the immunoreactive protein levels of CYP2B, CYP2C11, CYP3A, and NADPH-CYP reductase. These results indicate that a pharmacologically relevant concentration of doxorubicin does not cause direct mechanism-based inactivation of hepatic microsomal CYPs or NADPH-CYP reductase, suggesting that the ability of doxorubicin to depress hepatic CYP-mediated biotransformation in vivo is due to lipid peroxidation mediated heme destruction, altered heme metabolism, and (or) decreased expression of selected CYP enzymes.
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PMID:Lack of mechanism-based inactivation of rat hepatic microsomal cytochromes P450 by doxorubicin. 1054 22


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