Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.5.1.18 (glutathione S-transferase)
22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The objective of the present study was to evaluate the stability of cytochrome P450 enzymes and of the conjugation enzyme systems epoxide hydrolase, glucuronosyl transferase, sulphotransferase and glutathione S-transferase in precision-cut rat lung slices incubated in RPMI media for different time periods up to 72 h. Moreover, the effect of culturing of lung slices on total glutathione levels and glutathione reductase was also investigated. Monitoring of cytochrome P450 activity was achieved using established diagnostic probes, but when activity in the lung was low the maintenance of the various enzymes in culture was determined immunologically using Western blotting. The dealkylation of pentoxyresorufin declined markedly during the first 4h of incubation but in the case of ethoxyresorufin loss of activity was more gradual and less severe. Western blot analysis revealed that the rate of decrease in cytochrome P450 apoprotein levels was isoform-specific with CYP2E1 being the most stable and CYP3A the least stable. Generally, phase II activities, especially cytosolic sulphotransferase, were relatively more stable throughout the incubation period compared with cytochromes P450. Finally, glutathione reductase activity and total glutathione levels were maintained throughout the 72 h incubation. The present studies indicate that xenobiotic-metabolising enzymes in precision-cut rat lung slices decline in culture, but the rate of loss differs and depends on the nature of the enzyme.
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PMID:Stability of cytochromes P450 and phase II conjugation systems in precision-cut rat lung slices cultured up to 72 h. 1670 34

The synthetic antioxidant ethoxyquin (EQ) is increasingly used in animal feeds and has been candidate for carcinogenicity testing. EQ has the potential for toxicological and adverse health effects for both fish and fish consumers through "carryover" processes. The toxicological aspects of EQ have not been systematically investigated. The present study was performed to investigate the hepatic metabolism, metabolite characterization, and toxicological aspects of EQ in salmon during a 2-week depuration after a 12-week feeding period with 18 mg (low), 107 mg (medium), and 1800 mg/kg feed (high). The alteration in gene expressions and catalytic activities of hepatic biotransformation enzymes were studied using real-time polymerase chain reaction with specific primer pairs and by kinetics of two identified hepatic metabolites. Analysis of EQ metabolism was performed using high performance liquid chromatography (HPLC) method and showed the detection of four compounds of which two were quantified, parent EQ and EQ dimer (EQDM). Two metabolites were identified as de-ethylated EQ (DEQ) and quinone imine, but these were not quantified. The concentration of the quantified EQ-related compounds in the liver at day 0 showed a positive linear relationship with measured dietary EQ (R2= 0.86 and 0.92 for parent EQ and EQDM, respectively). While the low-EQ-feeding group showed a time-specific increase of aryl hydrocarbon receptor (AhR) mRNA expression, the medium-dose group showed decreased AhR mRNA at depuration day 7. Expression of CYP1A1 was decreased during the depuration period. Consumption of dietary EQ produced the expression of CYP3A, glutathione S-transferase (GST), and uridine diphosphate glucuronosyl-transferase (UDPGT) mRNA during the depuration period. A similar pattern of effect was observed for both CYP3A and phase II genes and supports our previous postulation of common regulation of these enzymes by the same inducer, namely EQ metabolites. The increase of CYP3A, UDPGT, and GST gene expressions at day 7 was in accordance with the low concentration of DEQ. The low concentration of putative DEQ may induce the CYP3A with subsequent increase in the biotransformation of EQ into DEQ. The increase in UDPGT may seem to be a synchronizing mechanism required for the excretion of DEQ. The biotransformation of dietary EQ is proven by simultaneous induction of both phase I and II detoxification system in the liver of Atlantic salmon. Therefore, the apparent low concentration of putative DEQ may account for the induced phase I and II detoxifying enzymes at least during depuration. This speculated hypothesis is currently a subject for systematic investigation in our laboratory using in vitro and genomic approaches.
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PMID:Hepatic biotransformation and metabolite profile during a 2-week depuration period in Atlantic salmon fed graded levels of the synthetic antioxidant, ethoxyquin. 1679 Apr 89

The effects of fungicide bitertanol on cytochrome P450-dependent monooxygenases were studied using rats treated intraperitoneally with the N-substituted triazole for 4 days. Treatment with 10, 25, and 100 mg/kg bitertanol produced 2-, 4-, and 14-fold increases of 7-ethoxyresorufin O-deethylation activity in liver microsomes, respectively. Immunoblot analysis of microsomal proteins revealed that 25 mg/kg bitertanol increased CYP1A1 protein in the liver, kidney, and lung by 10-, 13-, and 17-fold, respectively. Bitertanol produced smaller increases of CYP2B and CYP3A catalytic activity and protein than that of CYP1A1 in liver. RT-PCR analysis of total RNA indicated that bitertanol-induced CYP1A1, CYP2B, and CYP3A mRNA. Additions of 0.01-100 microM bitertanol to liver microsomes from rats treated with 25 mg/kg bitertanol or 3-methylcholanthrene inhibited microsomal 7-ethoxyresorufin O-deethylation activity (IC(50)=0.8 or 0.9 microM). Bitertanol at 100 mg/kg increased liver UDP-glucuronosyltransferase and glutathione S-transferase activities by 2-fold. Bitertanol at 25 mg/kg produced a minor increase in metabolic activation of benzo[a]pyrene by liver S-9 fraction in the Ames mutagenicity test while the increase was blocked by addition of 100 microM bitertanol. These findings show that bitertanol is an inducer of CYP1A1, CYP2B, and CYP3A in vivo and an inhibitor of CYP1A catalytic activity in vitro.
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PMID:Induction and inhibition of cytochrome P450-dependent monooxygenases of rats by fungicide bitertanol. 1697 Oct 34

During fetal development, the liver serves as the primary hematopoietic organ in which hematopoietic stem cells (HSC) capable of initiating long-term hematopoiesis comprise a large proportion of the hepatic cell population. Although HSC are potential targets for transplacental chemicals, little is known regarding their xenobiotic biotransformation ability. We quantitated the steady-state mRNA expression of six cytochrome P450 (P450) and 11 glutathione S-transferase (GST) isoforms in CD34(+)-selected HSC isolated from second trimester human fetal liver donors, genotyped donors for polymorphic hGSTM1 and hGSTT1 status, and analyzed gene expression in HSC relative to total liver from donors of similar gestational ages. Several P450 isoforms, including CYP1A1, CYP2E1, CYP3A4, and CYP3A5, were expressed at low levels in HSC (relative mRNA expression CYP3A5 > CYP1A1 > CYP2E1 > CYP3A4). CYP1A2 and CYP3A7 were not detected in HSC. The CYP3A4/5 mRNA expression in HSC was accompanied by detectable CYP3A protein and low midazolam oxidation activity. Several GST isoforms, including hGSTM1, hGSTM2, hGSTM4, and hGSTP1, were significantly higher in HSC as compared with total fetal liver. With the exception of hGSTA4, alpha class GST were not detected in HSC. GST expression in HSC was accompanied by substantial GST catalytic activity toward 1-chloro-2,4-dinitrobenzene. In summary, our data indicate that fetal liver CD34(+)-derived HSC constitutively express several P450 isoforms at low levels relative to total hepatic cell populations but have a higher capacity for GST conjugation reactions through mu and pi class isoforms. The functional ramifications of these observations are discussed relative to the sensitivity of human fetal HSC to transplacental chemical injury.
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PMID:Cytochrome p450 and glutathione s-transferase mRNA expression in human fetal liver hematopoietic stem cells. 1705 Jun 47

The synthetic antioxidant ethoxyquin (EQ) is a widely used additive in animal feeds, including farmed fish feed. The use of EQ as food additive is prohibited and it is also undesirable in farmed meat and fish products. The possible negative aspects of EQ in fish feeds, such as modulation of hepatic detoxifying enzymes and possible effects through "carry-over" to edible parts of fish are not known. In addition, the subsequent consequences for human consumers have not been previously studied. In the present work, the alteration in gene and protein expression patterns, and catalytic activities of phase I and II hepatic biotransformation enzymes due to prolonged exposure to graded levels of dietary EQ in the range of 11-1800 mg EQ/kg feed were studied. The kinetics of parent EQ and its major metabolite, ethoxyquin dimer (EQDM) was also studied. In general two weeks seem to be the critical point in the entire toxicological response of salmon to dietary consumed EQ. Biotransformation of EQ to EQDM is shown to be a rapid process. However, the decrease in biotransformation rate results in the accumulation of EQ metabolites, high concentration of which was postulated to alter translation and post-translational modification of CYP3A, GST and UDPGT at feeding day 14 and 42, with subsequent decreases in the biotransformation of consumed EQ. Decrease in the biotransformation of consumed EQ produced the retention of un-metabolized EQ rather than metabolites in salmon liver. This may be considered as undesirable effect, since it could lead to the transport and accumulation in other organs and edible tissues. It may also cause a new wave of biotransformation with formation of metabolites inhibiting detoxifying enzymes. In general, these processes may prolong the excretion of dietary EQ from the fish body and produce EQ-derived residues in the ready-to-consume salmon or fish products. These EQ residues may have higher toxicological effects for human consumers than the parent compound and therefore need to be studied in more detail.
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PMID:Hepatic metabolism, phase I and II biotransformation enzymes in Atlantic salmon (Salmo Salar, L) during a 12 week feeding period with graded levels of the synthetic antioxidant, ethoxyquin. 1715 Feb 95

Hydroxylated metabolites of PCBs [OH-PCBs] represent new health and environmental concern because they have been shown to have agonist or antagonist interactions with hormone receptors (HRs) or hormone-receptor mediated responses. The present study was designed to investigate the estrogenic potency based on anti-AhR signalling effect of three 4-OH substituted PCB congeners (#107, #146 and #187), one 3-OH substituted congener (#138), and the pharmaceutical synthetic estrogen, ethynylestradiol (EE2) in fish in vitro system using primary culture of Atlantic salmon hepatocytes. The effects were studied by quantifying changes in transcripts with gene-sequence primer pairs for a suite of gene responses (AhRalpha, ARNT, CYP1A1, CYP3A, UGT and GST) belonging to the xenobiotic biotransformation system. Our data show that OH-PCB congeners and EE2, decreased AhRalpha and ARNT transcript levels, and CYP1A1, UGT and GST gene expressions, together with CYP3A gene expression. The decreased expression of transcripts for xenobiotic biotransformation system is related to the concentration of individual OH-PCB congener and these responses are typical of reported estrogenic and estrogen-like effects on the CYP system. Modulation of biotransformation pathways by OH-PCBs may alter xenobiotic metabolism leading to the production of toxic reactive molecules, altering pharmacokinetics and diminishing the clearance rate of individual chemicals from the organism.
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PMID:Effects of hydroxy-polychlorinated biphenyl (OH-PCB) congeners on the xenobiotic biotransformation gene expression patterns in primary culture of Atlantic salmon (Salmo salar) hepatocytes. 1720 28

Multiple biological effects of tributyltin (TBT) on juvenile salmon have been investigated. Fish were exposed for 7 days to waterborne TBT at nominal concentrations of 50 and 250 microg/L dissolved in dimethyl sulfoxide (DMSO). Hepatic samples were analyzed for gene expression patterns in the hormonal and xenobiotic biotransformation pathways using validated real-time PCR method. Immunochemical and several cytochrome P450 (CYP)-mediated enzyme activity (ethoxyresorufin: EROD, benzyloxyresorufin: BROD, methoxyresorufin: MROD and pentoxyresorufin: PROD) assays were analyzed. Our data show that TBT produced concentration-specific decrease of estrogen receptor-alpha (ERalpha), vitellogenin (Vtg), zona radiata protein (Zr-protein) and increase of estrogen receptor-beta (ERbeta) and androgen receptor-beta (ARbeta) in the hormonal pathway. In the xenobiotic biotransformation pathway, TBT produced apparent increase and decrease at respective low and high concentration, on aryl hydrocarbon receptor-alpha (AhRalpha), AhR nuclear translocator (ARNT) and AhR repressor (AhRR) mRNA. The expression of CYP1A1 and GST showed a TBT concentration-dependent decrease. The AhRbeta, CYP3A and uridine diphosphoglucuronosyl transferase (UGT) mRNA expressions were significantly induced after exposure to TBT. Immunochemical analysis of CYP3A and CYP1A1 protein levels confirmed the TBT effects observed at the transcriptional levels. The effect of TBT on the biotransformation enzyme gene expressions partially co-related but did not directly parallel enzyme activity levels for EROD, BROD, MROD and PROD. In general, these findings confirm previous reports on the endocrine effects of TBT, in addition to effects on hepatic CYP1A isoenzyme at the transcriptional level that transcends to protein and enzymatic levels. The induced expression patterns of CYP3A and UGT mRNA after TBT exposure, suggest the involvement of CYP3A and UGT in TBT metabolism in fish. The effect of TBT on CYP3A is proposed to represent another hormonal effect of TBT not previously reported in any fish or lower vertebrate. The proposed androgenic effect is supported by the observation that TBT also induced ARbeta mRNA expression in a concentration-specific manner. To our knowledge, this is the first study that has simultaneously studied multiple responses after exposure to TBT in fish.
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PMID:Modulation of xenobiotic biotransformation system and hormonal responses in Atlantic salmon (Salmo salar) after exposure to tributyltin (TBT). 1734 1

Dichloromethane (DCM) is metabolically converted to carbon monoxide mostly by CYP2E1 in liver, resulting in elevation of blood carboxyhemoglobin (COHb) levels. We investigated the effects of a subtoxic dose of acetaminophen (APAP) on the metabolic elimination of DCM and COHb elevation in adult female rats. APAP, at 500 mg/kg i.p., was not hepatotoxic as measured by a lack of change in serum aspartate aminotransferase, alanine aminotransferase, and sorbitol dehydrogenase activities. In rats pretreated with APAP at this dose, the COHb elevation resulting from administration of DCM (3 mmol/kg i.p.) was enhanced significantly. Also blood DCM levels were reduced, and its disappearance from blood appeared to be increased. Hepatic CYP2E1-mediated activities measured with chlorzoxazone, p-nitrophenol, and p-nitroanisole as substrates were all induced markedly in microsomes of rats treated with APAP. Aminopyrine N-demethylase activity was also increased slightly, but significantly. Western blot analysis showed that APAP treatment induced the expression of CYP2E1 and CYP3A proteins. Neither hepatic glutathione contents nor glutathione S-transferase activity was changed by the dose of APAP used. The results indicate that, contrary to the well known hepatotoxic effects of this drug at large doses, a subtoxic dose of APAP may induce CYP2E1, and to a lesser degree, CYP3A expression. This is the first report that APAP can increase cytochrome P450 (P450)-mediated hepatic metabolism and the resulting toxicity of a xenobiotic in the whole animal. The pharmacological/toxicological significance of induction of P450s by a subtoxic dose of APAP is discussed.
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PMID:Induction of hepatic CYP2E1 by a subtoxic dose of acetaminophen in rats: increase in dichloromethane metabolism and carboxyhemoglobin elevation. 1762 Mar 48

Pharmaceuticals are ubiquitous pollutants in the aquatic environment where their potential effects on non-target species like fish has only recently become subject of systematic investigations. In the present study, experiments were undertaken to examine the effects of a synthetic pharmaceutical endocrine disruptor, ethynylestradiol (EE2), given in water at 5 or 50 ng/L and sampled at days 0 (control), 3 and 7 after exposure, on hepatic phase I and II biotransformation and hormonal pathways of juvenile salmon using quantitative (real-time) polymerase chain reaction (qPCR), Vtg ELISA and 7-ethoxyresorufin O-deethylase (EROD) catalytic activity. Our data show that EE2 produced time- and concentration-specific modulation of estrogen receptor isoforms (ERalpha, ERbeta) and androgen receptor-beta (ARbeta). EE2 produced a concentration-specific induction of vitellogenin (Vtg) and zona radiata protein (Zr-protein) at day 3 after exposure. At day 7, Vtg and Zr-protein mRNA (and plasma Vtg protein) expression were significantly decreased in the group given 5 ng EE2/L, compared to dimethyl sulfoxide (DMSO) control group. In the xenobiotic biotransformation pathway, EE2 produced a significant increase of aryl hydrocarbon receptor-alpha (AhRalpha) at day 3 in the group given 5 ng EE2/L and AhRbeta was decreased at the same concentration at day 7. While CYP3A was not significantly affected by EE2 exposure, the CYP1A1, AhR nuclear translocator (Arnt) and AhR repressor (AhRR) mRNA showed an apparent EE2 concentration and time-dependent decrease. The expression of uridine diphosphoglucuronosyl transferase (UGT) and glutathione S-transferase class pi-like (GSTpi-like) mRNA were decreased after exposure to 50ng EE2/L at both day 3 and 7 after exposure. The effect of EE2 on the CYP1A1 gene expressions paralleled effect on EROD and AhRR mRNA, suggesting a direct role of EE2 in controlling cellular detoxification machinery. Interestingly, the carrier vehicle, DMSO produced significant time-dependent induction of estrogenic (ERalpha, Vtg and Zr-protein) responses, compared with blank (i.e. without DMSO) controls at day 7 post-exposure. The effect of DMSO totally underscored the observed EE2 effect at day 7 after exposure. In general, these findings support previous reports on the endocrine effects of EE2, in addition to effects on hepatic biotransformation system. In view of the data presented here and our recent studies, the use of DMSO as carrier vehicle in endocrine toxicological experimental studies should be re-evaluated.
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PMID:Effects of 17alpha-ethynylestradiol on hormonal responses and xenobiotic biotransformation system of Atlantic salmon (Salmo salar). 1787 31

The challenge of consuming plant compounds that are recognized to have toxic physiological effects is an unavoidable consequence of an herbivorous diet and requires mechanisms to metabolize and eliminate them after consumption. We took a pharmacological approach to understanding how an oak (Quercus agrifolia) specialist (Neotoma macrotis) and generalist (N. lepida) herbivores process the same dietary toxins. Oak contains polyphenolic compounds considered toxic to most other mammals. N. macrotis includes up to 85% of oak in their diet. N. lepida includes oak as a portion of the diet but is considered a generalist in areas where sympatric with N. macrotis. Xenobiotic metabolizing enzyme activities of N. macrotis and N. lepida were investigated after animals were fed a 70% oak diet and a toxin-free control diet. Biotransformation activities of five major enzymes [cytochrome P450s (CYP), NAD(P)H/quinone oxidoreductase (QOR), UDP-glucuronosyltransferase (UGT), sulfotransferase (SULT), and glutathione S-transferase (GST)] and three specific CYP isozymes (CYP1A, CYP2B, and CYP3A) were investigated. The results indicate that, with the exception of CYP2B induction, N. macrotis and N. lepida enzyme activities are not changed by an oak diet. The major differences in enzyme activities were constitutive. The specialist, N. macrotis, had higher constitutive activity of QOR, UGT, and GST. The generalist, N. lepida, had higher constitutive activity levels of CYP1A and SULT.
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PMID:Xenobiotic metabolism of plant secondary compounds in oak (Quercus agrifolia) by specialist and generalist woodrat herbivores, genus Neotoma. 1792 91


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