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Article: Risk assessment: toxicity from chemical exposure resulting from enhanced expression of CYP2E1.

Raucy, J L

1995 Volume 105, Issue 2-3, Page(s) 217–224

Abstract: Humans are continuously exposed to a wide variety of xenobiotics either voluntarily or from environmental exposure. Many xenobiotics including pesticides, nitrosamines, polycyclic aromatic hydrocarbons and halogenated hydrocarbons, require bioactivation ... ...

Abstract	Humans are continuously exposed to a wide variety of xenobiotics either voluntarily or from environmental exposure. Many xenobiotics including pesticides, nitrosamines, polycyclic aromatic hydrocarbons and halogenated hydrocarbons, require bioactivation by P450 enzymes to elicit toxicity. CYP2E1 is considered to be toxicologically important in humans because of its capacity to produce intermediates that promote cytotoxicity and/or carcinogenicity from a number of xenobiotics. Importantly, CYP2E1 is present constitutively and its content can be modulated by a variety of factors including xenobiotics such as alcohol. Because hepatic concentrations of CYP2E1 can vary considerably from one individual to another, the extent of formation of toxic products also varies. Indeed, as hepatic concentrations increase so does the risk of toxicity from chemicals activated by this P450 enzyme. Many chemicals modulate CYP2E1 expression and exposure to one compound may alter the toxicological impact of another. Considering that CYP2E1 content is related to toxicity from chemicals, identifying subjects with elevated levels may lead to minimizing exposure in high risk individuals.
MeSH term(s)	Biotransformation ; Cytochrome P-450 CYP2E1 ; Cytochrome P-450 Enzyme System/biosynthesis ; Cytochrome P-450 Enzyme System/metabolism ; Environmental Exposure ; Enzyme Induction ; Hazardous Substances/adverse effects ; Hazardous Substances/metabolism ; Humans ; Liver/enzymology ; Oxidoreductases, N-Demethylating/biosynthesis ; Oxidoreductases, N-Demethylating/metabolism ; Risk Assessment ; Xenobiotics/adverse effects ; Xenobiotics/metabolism
Chemical Substances	Hazardous Substances ; Xenobiotics ; Cytochrome P-450 Enzyme System (9035-51-2) ; Cytochrome P-450 CYP2E1 (EC 1.14.13.-) ; Oxidoreductases, N-Demethylating (EC 1.5.-)
Language	English
Publishing date	1995-12-28
Publishing country	Ireland
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S. ; Review
ZDB-ID	184557-3
ISSN	1879-3185 ; 0300-483X
ISSN (online)	1879-3185
ISSN	0300-483X
DOI	10.1016/0300-483x(95)03216-3
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Zs.A 888: Show issues

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Article: Recent advances in P450 research.

Raucy, J L / Allen, S W

The pharmacogenomics journal

2001 Volume 1, Issue 3, Page(s) 178–186

Abstract: P450 enzymes comprise a superfamily of heme-containing proteins that catalyze oxidative metabolism of structurally diverse chemicals. Over the past few years, there has been significant progress in P450 research on many fronts and the information gained ... ...

Abstract	P450 enzymes comprise a superfamily of heme-containing proteins that catalyze oxidative metabolism of structurally diverse chemicals. Over the past few years, there has been significant progress in P450 research on many fronts and the information gained is currently being applied to both drug development and clinical practice. Recently, a major accomplishment occurred when the structure of a mammalian P450 was determined by crystallography. Results from these studies will have a major impact on understanding structure-activity relationships of P450 enzymes and promote prediction of drug interactions. In addition, new technologies have facilitated the identification of several new P450 alleles. This information will profoundly affect our understanding of the causes attributed to interindividual variations in drug responses and link these differences to efficacy or toxicity of many therapeutic agents. Finally, the recent accomplishments towards constructing P450 null animals have afforded determination of the role of these enzymes in toxicity. Moreover, advances have been made towards the construction of humanized transgenic animals and plants. Overall, the outcome of recent developments in the P450 arena will be safer and more efficient drug therapies.
MeSH term(s)	Animals ; Animals, Genetically Modified/genetics ; Animals, Genetically Modified/metabolism ; Cytochrome P-450 Enzyme System/chemistry ; Cytochrome P-450 Enzyme System/genetics ; Humans ; Multigene Family ; Polymorphism, Genetic/genetics
Chemical Substances	Cytochrome P-450 Enzyme System (9035-51-2)
Language	English
Publishing date	2001-05-02
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2106831-8
ISSN	1473-1150 ; 1470-269X
ISSN (online)	1473-1150
ISSN	1470-269X
DOI	10.1038/sj.tpj.6500044
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Zs.A 5806: Show issues

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Article ; Online: Critères cliniques en faveur d’un portage de germe pathogène chez le nouveau-né à terme suspect d’infection néonatale bactérienne précoce.

Glusko-Charlet, A / Fontaine, C / Raucy, M / Barcat, L / Lahana, A / Erbani, R / Poirie, G / Kongolo, G / Diouf, M / Leke, A / Gondry, J / Tourneux, P

Archives de pediatrie : organe officiel de la Societe francaise de pediatrie

2017 Volume 24, Issue 10, Page(s) 934–941

Abstract: Background: Neonatal early onset sepsis (EOS) remains an important etiology of neonatal morbidity and mortality. Diagnosis is difficult due to a lack of sensitivity and specificity markers. In France, the management of newborn infants suspected of ... ...

Title translation	Clinical criteria for pathogen bacteria in term newborn suspected of neonatal sepsis.
Abstract	Background: Neonatal early onset sepsis (EOS) remains an important etiology of neonatal morbidity and mortality. Diagnosis is difficult due to a lack of sensitivity and specificity markers. In France, the management of newborn infants suspected of infection includes the analysis of gastric suction. The objective of the study was to identify early clinical signs in newborn infants with suspected neonatal sepsis to differentiate a likely infection with pathogen bacteria in the gastric suction culture (Streptococcus agalactiae or Escherichia coli) from a possible infection without such pathogen bacteria. Methods: We conducted a retrospective study in the Amiens University Hospital. All term newborn infants born between 1 January and 31 December 2013 and hospitalized for suspected EOS were included. Suspicion of EOS was considered when there were arguments to treat by antibiotics for a period of at least 5 days. Results: Fifty-eight newborn infants were included, 25 had a likely EOS and 33 a possible EOS. Newborn infants with a likely EOS were less mature (P<0.01) with more clinical signs at birth (P<0.01). The most common clinical signs were: hyperthermia (P=0.01), somnolence (P<0.01), and hypotonia (P=0.01). After adjusting for the term, the presence of hyperthermia was no longer significantly different between the two groups (P=0.059), the other clinical signs remained significantly different. Conclusion: The presence of neonatal symptoms at birth appears to be a useful clinical marker of probable neonatal EOS.
MeSH term(s)	Bacteria/pathogenicity ; Bacterial Infections/diagnosis ; Bacterial Infections/microbiology ; Female ; Humans ; Infant, Newborn ; Male ; Neonatal Sepsis/diagnosis ; Neonatal Sepsis/microbiology ; Retrospective Studies
Language	French
Publishing date	2017-10
Publishing country	France
Document type	Journal Article
ZDB-ID	1181947-9
ISSN	1769-664X ; 0929-693X
ISSN (online)	1769-664X
ISSN	0929-693X
DOI	10.1016/j.arcped.2017.07.009
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Zs.A 3942: Show issues

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Article: The expression of xenobiotic-metabolizing cytochromes P450 in fetal tissues.

Raucy, J L / Carpenter, S J

Journal of pharmacological and toxicological methods

1993 Volume 29, Issue 3, Page(s) 121–128

MeSH term(s)	Animals ; Cytochrome P-450 Enzyme System/metabolism ; Fetus/enzymology ; Humans ; Xenobiotics/metabolism
Chemical Substances	Xenobiotics ; Cytochrome P-450 Enzyme System (9035-51-2)
Language	English
Publishing date	1993-06
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S. ; Review
ZDB-ID	1105919-9
ISSN	1873-488X ; 1056-8719
ISSN (online)	1873-488X
ISSN	1056-8719
DOI	10.1016/1056-8719(93)90062-j
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Zs.A 1440: Show issues

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Article: Isolation of P450 enzymes from human liver.

Raucy, J L / Lasker, J M

Methods in enzymology

1991 Volume 206, Page(s) 577–587

MeSH term(s)	Adult ; Cell Fractionation/methods ; Chromatography/methods ; Chromatography, Affinity/methods ; Chromatography, DEAE-Cellulose/methods ; Chromatography, Ion Exchange/methods ; Cytochrome P-450 Enzyme System/isolation & purification ; Cytochrome P-450 Enzyme System/metabolism ; Durapatite ; Electrophoresis, Polyacrylamide Gel/methods ; Female ; Humans ; Hydroxyapatites ; Indicators and Reagents ; Isoenzymes/isolation & purification ; Isoenzymes/metabolism ; Kinetics ; Male ; Microsomes, Liver/enzymology ; Molecular Weight ; Substrate Specificity ; Ultracentrifugation/methods
Chemical Substances	Hydroxyapatites ; Indicators and Reagents ; Isoenzymes ; Cytochrome P-450 Enzyme System (9035-51-2) ; Durapatite (91D9GV0Z28)
Language	English
Publishing date	1991
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ISSN	0076-6879
ISSN	0076-6879
DOI	10.1016/0076-6879(91)06127-o
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Article: Regulation of CYP2E1 by ethanol and palmitic acid and CYP4A11 by clofibrate in primary cultures of human hepatocytes.

Raucy, Judy L / Lasker, Jerome / Ozaki, Kazuaki / Zoleta, Veronica

Toxicological sciences : an official journal of the Society of Toxicology

2004 Volume 79, Issue 2, Page(s) 233–241

Abstract: CYP2E1 and CYP4A11 are cytochrome P450 enzymes that are regulated by physiological conditions including diabetes and fasting. In addition, the xenochemical clofibrate has been reported to induce both rodent CYP2E1 and CYP4A. These findings suggest ... ...

Abstract	CYP2E1 and CYP4A11 are cytochrome P450 enzymes that are regulated by physiological conditions including diabetes and fasting. In addition, the xenochemical clofibrate has been reported to induce both rodent CYP2E1 and CYP4A. These findings suggest similar modes of regulation. Also in common to both enzymes is the ability to metabolize fatty acids such as laurate and arachidonic acid. Here, we used primary cultures of human hepatocytes to determine if certain xenochemicals could regulate CYP2E1 and CYP4A11. Ethanol significantly (p < 0.05) increased expression of CYP2E1 mRNA by 216 +/- 32% of control, but did not alter CYP4A11 mRNA accumulation (145 +/- 22% of control). In contrast, hepatocytes exposed to ethanol exhibited only a slight elevation in CYP2E1 protein (122 +/- 13% of control) and a negligible effect on CYP4A11 protein. Clofibrate significantly (p < 0.05) enhanced both CYP4A11 mRNA and protein by 239 +/- 30% and 154 +/- 10% of control, respectively, but did not increase CYP2E1. Because rodent CYP4A is reportedly regulated by fatty acids through peroxisome proliferator activated receptor alpha (PPARalpha) and CYP2E1 is induced by high fat diets, we examined the effects of a medium chain fatty acid, palmitate on CYP2E1 mRNA content. Palmitic acid significantly (p < 0.05) increased CYP2E1 mRNA to 326 +/- 57% of control. Collectively, results presented here identify agents that enhance CYP2E1 and CYP4A11 at the transcription level and suggest that fatty acids may represent a similar mode of regulation for these P450 enzymes. The lack of induction of CYP2E1 protein by ethanol in human hepatocytes indicates that for certain P450 enzymes, isolated hepatocytes may not be an adequate tool for predicting in vivo responses.
MeSH term(s)	Adolescent ; Adult ; Aged ; Blotting, Northern ; Blotting, Western ; Cells, Cultured ; Child ; Child, Preschool ; Clofibrate/pharmacology ; Cytochrome P-450 CYP2E1/biosynthesis ; Cytochrome P-450 CYP2E1/genetics ; Cytochrome P-450 CYP4A ; Cytochrome P-450 Enzyme System/biosynthesis ; Cytochrome P-450 Enzyme System/genetics ; Ethanol/pharmacology ; Female ; Gene Expression Regulation, Enzymologic/drug effects ; Hepatocytes/drug effects ; Hepatocytes/enzymology ; Humans ; Male ; Middle Aged ; Palmitic Acid/pharmacology ; RNA, Messenger/analysis ; RNA, Messenger/biosynthesis
Chemical Substances	RNA, Messenger ; Palmitic Acid (2V16EO95H1) ; Ethanol (3K9958V90M) ; Cytochrome P-450 Enzyme System (9035-51-2) ; Cytochrome P-450 CYP2E1 (EC 1.14.13.-) ; CYP4A11 protein, human (EC 1.14.15.3) ; Cytochrome P-450 CYP4A (EC 1.14.15.3) ; Clofibrate (HPN91K7FU3)
Language	English
Publishing date	2004-06
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfh126
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Zs.A 1709: Show issues

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Article: Expression, induction, and catalytic activity of the ethanol-inducible cytochrome P450 (CYP2E1) in human fetal liver and hepatocytes.

Carpenter, S P / Lasker, J M / Raucy, J L

Molecular pharmacology

1996 Volume 49, Issue 2, Page(s) 260–268

Abstract: The mechanisms responsible for ethanol-mediated teratogenesis have not been resolved. However, possible etiologies include the local formation of the teratogen acetaldehyde or oxygen radicals by fetal ethanol-oxidizing enzymes. As alcohol dehydrogenases ... ...

Abstract	The mechanisms responsible for ethanol-mediated teratogenesis have not been resolved. However, possible etiologies include the local formation of the teratogen acetaldehyde or oxygen radicals by fetal ethanol-oxidizing enzymes. As alcohol dehydrogenases are expressed at very low concentrations in human embryonic tissues, the ethanol-inducible P450 enzyme, CYP2E1, could be the sole catalyst of fetal ethanol oxidation. With this in mind, we examined the expression of this P450 in liver samples from fetuses ranging in gestational age from 16 to 24 weeks. Immunoblot analysis of fetal liver microsomes revealed the presence of a protein immunoreactive with CYP2E1 antibodies that exhibited a slightly lower molecular weight than that found in adult liver samples. Embryonic CYP2E1 expression was further confirmed by the reverse transcriptase reaction with RNA from a 19-week gestational fetal liver used as template. Catalytic capabilities of human fetal microsomes were assessed by measurement of the rate of ethanol oxidation to acetaldehyde, which were 12-27% of those exhibited by adult liver microsomes. Immunoinhibition studies with CYP2E1 antibodies revealed that the corresponding antigen was the major catalyst of this reaction in both fetal and adult tissues. We then assessed whether embryonic CYP2E1 was, like the adult enzyme, inducible by xenobiotics. Treatment of primary fetal hepatocyte cultures with either ethanol or clofibrate demonstrated a 2-fold increase in CYP2E1 levels compared with untreated cells. Collectively, our results indicate that CYP2E1 is present in human fetal liver, that the enzyme is functionally similar to CYP2E1 from adults, and that fetal hepatocyte CYP2E1 is inducible in culture by xenobiotics, including ethanol. Because fetal CYP2E1 mediates ethanol metabolism, the enzyme may play a pivotal role in the local production of acetaldehyde and free radicals, both of which have potential deleterious effects on the developing fetus.
MeSH term(s)	Adult ; Cells, Cultured ; Cytochrome P-450 CYP2E1 ; Cytochrome P-450 Enzyme System/biosynthesis ; Cytochrome P-450 Enzyme System/metabolism ; Embryonic and Fetal Development ; Enzyme Induction ; Enzyme Stability ; Ethanol/metabolism ; Ethanol/pharmacology ; Fetus ; Gene Expression Regulation, Developmental ; Gestational Age ; Humans ; Immunohistochemistry ; Kinetics ; Liver/drug effects ; Liver/embryology ; Liver/enzymology ; Microsomes, Liver/enzymology ; Oxidoreductases, N-Demethylating/biosynthesis ; Oxidoreductases, N-Demethylating/metabolism ; Polymerase Chain Reaction ; Templates, Genetic
Chemical Substances	Ethanol (3K9958V90M) ; Cytochrome P-450 Enzyme System (9035-51-2) ; Cytochrome P-450 CYP2E1 (EC 1.14.13.-) ; Oxidoreductases, N-Demethylating (EC 1.5.-)
Language	English
Publishing date	1996-02
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	124034-1
ISSN	1521-0111 ; 0026-895X
ISSN (online)	1521-0111
ISSN	0026-895X
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Zs.A 525: Show issues

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Article: CYP2C19 participates in tolbutamide hydroxylation by human liver microsomes.

Wester, M R / Lasker, J M / Johnson, E F / Raucy, J L

Drug metabolism and disposition: the biological fate of chemicals

2000 Volume 28, Issue 3, Page(s) 354–359

Abstract: Tolbutamide is a sulfonylurea-type oral hypoglycemic agent whose action is terminated by hydroxylation of the tolylsulfonyl methyl moiety catalyzed by cytochrome P-450 (CYP) enzymes of the human CYP2C subfamily. Although most studies have implicated ... ...

Abstract	Tolbutamide is a sulfonylurea-type oral hypoglycemic agent whose action is terminated by hydroxylation of the tolylsulfonyl methyl moiety catalyzed by cytochrome P-450 (CYP) enzymes of the human CYP2C subfamily. Although most studies have implicated CYP2C9 as the exclusive catalyst of hepatic tolbutamide hydroxylation in humans, there is evidence that other CYP2C enzymes (e.g., CYP2C19) may also participate. To that end, we used an immunochemical approach to assess the role of individual CYP2Cs in microsomal tolbutamide metabolism. Polyclonal antibodies were raised to CYP2C9 purified from human liver, and were then back-adsorbed against recombinant CYP2C19 coupled to a solid-phase support. Western blotting revealed that the absorbed anti-human CYP2C9 preparation reacted with only recombinant CYP2C9 and the corresponding native protein in hepatic microsomes, and no longer recognized CYP2C19 and CYP2C8. Monospecific anti-CYP2C9 not only retained the ability to inhibit CYP2C9-catalyzed reactions, as evidenced by its marked (90%) inhibition of diclofenac 4'-hydroxylation by purified CYP2C9 and by human liver microsomes, but also exhibited metabolic specificity, as indicated by its negligible (<15%) inhibitory effect on S-mephenytoin 4'-hydroxylation by purified CYP2C19 or hepatic microsomes containing CYP2C19. Monospecific anti-CYP2C9 was also found to inhibit rates of tolbutamide hydroxylation by 93 +/- 4 and 78 +/- 6% in CYP2C19-deficient and CYP2C19-containing human liver microsomes, respectively. Taken together, our results indicate that both CYP2C9 and CYP2C19 are involved in tolbutamide hydroxylation by human liver microsomes, and that CYP2C19 underlies at least 14 to 22% of tolbutamide metabolism. Although expression of CYP2C19 in human liver is less than that of CYP2C9, it may play an important role in tolbutamide disposition in subjects expressing either high levels of CYP2C19 or a catalytically deficient CYP2C9 enzyme.
MeSH term(s)	Animals ; Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/isolation & purification ; Antibodies, Monoclonal/pharmacology ; Aryl Hydrocarbon Hydroxylases ; Cross Reactions ; Cytochrome P-450 CYP2C19 ; Cytochrome P-450 CYP2C8 ; Cytochrome P-450 CYP2C9 ; Cytochrome P-450 Enzyme System/immunology ; Cytochrome P-450 Enzyme System/metabolism ; Diclofenac/metabolism ; Humans ; Hydroxylation/drug effects ; Male ; Mephenytoin/metabolism ; Microsomes, Liver/drug effects ; Microsomes, Liver/metabolism ; Mixed Function Oxygenases/immunology ; Mixed Function Oxygenases/metabolism ; Rabbits ; Steroid 16-alpha-Hydroxylase ; Steroid Hydroxylases/immunology ; Steroid Hydroxylases/metabolism ; Tolbutamide/metabolism
Chemical Substances	Antibodies, Monoclonal ; cytochrome P-450 CYP2C subfamily ; Diclofenac (144O8QL0L1) ; Cytochrome P-450 Enzyme System (9035-51-2) ; Tolbutamide (982XCM1FOI) ; Mixed Function Oxygenases (EC 1.-) ; Steroid Hydroxylases (EC 1.14.-) ; CYP2C9 protein, human (EC 1.14.13.-) ; Cytochrome P-450 CYP2C9 (EC 1.14.13.-) ; Aryl Hydrocarbon Hydroxylases (EC 1.14.14.1) ; CYP2C19 protein, human (EC 1.14.14.1) ; CYP2C8 protein, human (EC 1.14.14.1) ; Cytochrome P-450 CYP2C19 (EC 1.14.14.1) ; Cytochrome P-450 CYP2C8 (EC 1.14.14.1) ; Steroid 16-alpha-Hydroxylase (EC 1.14.14.1) ; Mephenytoin (R420KW629U)
Language	English
Publishing date	2000-03
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	186795-7
ISSN	1521-009X ; 0090-9556
ISSN (online)	1521-009X
ISSN	0090-9556
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Zs.A 1014: Show issues

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Article: A cell-based reporter gene assay for determining induction of CYP3A4 in a high-volume system.

Raucy, Judy / Warfe, Lyndon / Yueh, Mei-Fei / Allen, Scott W

The Journal of pharmacology and experimental therapeutics

2002 Volume 303, Issue 1, Page(s) 412–423

Abstract: Assessing the inducibility of CYP3A4 by various xenobiotics can predict potential drug interactions. In the present investigation, human hepatoma cells were stably integrated with either the CYP3A4 enhancer region and a luciferase reporter gene or the ... ...

Abstract	Assessing the inducibility of CYP3A4 by various xenobiotics can predict potential drug interactions. In the present investigation, human hepatoma cells were stably integrated with either the CYP3A4 enhancer region and a luciferase reporter gene or the CYP3A4-luciferase construct and the human pregnane X receptor (PXR). Several colonies containing one to three copies of luciferase per cell were identified by Southern blot analysis. Those transformants producing high luciferase activity in response to rifampicin were used to standardize a 96-well plate screening system with minimal inter- and intraplate variability. Standardization also consisted of assessing viability of cells cultured in medium containing various serum concentrations. In cells maintained for 48 h in medium with less than 5% serum, a significant (p < 0.01) decline was observed in viability accompanied by altered induction. A defined serum-free medium also produced less viable cells but did not alter the inductive response. Treatment of transformants with various concentrations of rifampicin produced a dose-response curve with maximal induction at 10 microM (5.6 +/- 0.18- and 2.1 +/- 0.3-fold above dimethyl sulfoxide (DMSO)-treated cells in transformants with and without PXR, respectively). Of additional agents examined for their ability to induce CYP3A4, omeprazole (200 microM) was the most potent inducer (12.8 +/- 1.9- and 2.4 +/- 0.2-fold above DMSO-treated cells in transformants with and without PXR, respectively). Mifepristone and mevastatin produced modest induction (approximately 3-fold) in the cell line containing exogenous PXR, but produced less than 1.2-fold increases in cells lacking PXR. Thus, only potent inducers can be identified in the cell line without PXR. In contrast, cells containing the receptor can be used to rank CYP3A4 induction. Because a high volume of chemicals can be readily and accurately screened for their ability to induce CYP3A4 with this format, such a system could be valuable in the initial stages of preclinical drug development.
MeSH term(s)	Base Sequence ; Blotting, Northern ; Cell Line, Transformed ; Cell Survival/physiology ; Cytochrome P-450 CYP3A ; Cytochrome P-450 Enzyme System/biosynthesis ; Cytochrome P-450 Enzyme System/genetics ; DNA Primers ; Enzyme Induction ; Genes, Reporter ; Hepatocytes/metabolism ; Humans ; Liver/metabolism ; Lovastatin/analogs & derivatives ; Lovastatin/pharmacology ; Luciferases/genetics ; Mifepristone/pharmacology ; Mixed Function Oxygenases/biosynthesis ; Mixed Function Oxygenases/genetics ; Omeprazole/pharmacology ; Polychlorinated Dibenzodioxins/pharmacology ; Pregnane X Receptor ; RNA, Messenger/genetics ; Receptors, Cytoplasmic and Nuclear/genetics ; Receptors, Steroid/genetics ; Recombinant Fusion Proteins/biosynthesis ; Reverse Transcriptase Polymerase Chain Reaction ; Rifampin/pharmacology ; Transcription, Genetic/drug effects ; Transfection/methods
Chemical Substances	DNA Primers ; Polychlorinated Dibenzodioxins ; Pregnane X Receptor ; RNA, Messenger ; Receptors, Cytoplasmic and Nuclear ; Receptors, Steroid ; Recombinant Fusion Proteins ; mevastatin (1UQM1K0W9X) ; Mifepristone (320T6RNW1F) ; Cytochrome P-450 Enzyme System (9035-51-2) ; Lovastatin (9LHU78OQFD) ; Mixed Function Oxygenases (EC 1.-) ; Luciferases (EC 1.13.12.-) ; CYP3A protein, human (EC 1.14.14.1) ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; CYP3A4 protein, human (EC 1.14.14.55) ; Omeprazole (KG60484QX9) ; Rifampin (VJT6J7R4TR)
Language	English
Publishing date	2002-09-10
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.102.038653
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Uf I Zs.40: Show issues

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Article: Use of lymphocytes for assessing ethanol-mediated alterations in the expression of hepatic cytochrome P4502E1.

Raucy, J L / Curley, G / Carpenter, S P

Alcoholism, clinical and experimental research

1995 Volume 19, Issue 6, Page(s) 1369–1375

Abstract: The ethanol-inducible cytochrome P4502E1 (2E1) is involved in the bioactivation of numerous hepatotoxins and hepatocarcinogens. Because high levels of expression may enhance the degree and severity of hepatotoxicity from exposure to chemicals metabolized ...

Abstract	The ethanol-inducible cytochrome P4502E1 (2E1) is involved in the bioactivation of numerous hepatotoxins and hepatocarcinogens. Because high levels of expression may enhance the degree and severity of hepatotoxicity from exposure to chemicals metabolized by this enzyme, a relatively noninvasive method to phenotypically distinguish those individuals exhibiting elevated concentrations of 2E1 may be useful. With this in mind, we examined whether ethanol exposure could alter 2E1 in rabbit white blood cells and liver in a similar manner. Microsomes prepared from freshly isolated, rather than cultured cells, were used to immunochemically detect 2E1. The enzyme was found in lymphocytes and neutrophils. Lymphocytes, which comprise the majority of the white cell population in rabbits, were monitored for changes in 2E1 protein levels after ethanol exposure and compared with alterations of the hepatic enzyme. Results presented herein demonstrate that the degree of enhancement in 2E1 expression of lymphocytes and liver was dependent on the length and dose of alcohol exposure. Indeed, correlations were observed between blood alcohol concentrations and 2E1 content in lymphocytes (r = 0.65, p < 0.01) and liver (r = 0.60, p < 0.01). The greatest increase in 2E1 (6- to 10-fold) occurred in both liver and lymphocytes at a dose of 15% ethanol for 12 days of treatment. This induction was evident regardless of whether blood was taken from treated and compared with untreated rabbits or if white cells were obtained from the same animal before and after ethanol exposure. The latter findings demonstrate that changes in lymphocyte 2E1 were caused by ethanol exposure and not to variability in enzyme expression among rabbits. Interestingly, at the 10% dose, elevation of 2E1 was noted as early as 3 days, declined at 6 days, and at 12 and 24 days returned to slightly higher levels than those seen at the 3-day exposure period. This pattern of 2E1 elevation was observed in both the liver and lymphocytes. In fact, at all exposure periods and at the two doses of alcohol examined, a correlation (r = 0.70, p < 0.01) was observed between lymphocyte and liver 2E1 content. Collectively, these studies show that induction of 2E1 in lymphocytes and liver occurs in a parallel fashion. Furthermore, results suggest that blood 2E1 may be used in humans as a phenotypic marker for xenobiotic-promoted alterations in the expression of the liver enzyme. These findings should have a significant impact on in vivo monitoring of this P450 enzyme.
MeSH term(s)	Alcoholism/enzymology ; Alcoholism/genetics ; Animals ; Cytochrome P-450 CYP2E1 ; Cytochrome P-450 Enzyme System/genetics ; Enzyme Induction/genetics ; Ethanol/pharmacokinetics ; Gene Expression Regulation, Enzymologic/physiology ; Genetic Markers/genetics ; Lymphocytes/enzymology ; Microsomes, Liver/enzymology ; Oxidoreductases, N-Demethylating/genetics ; Phenotype ; Rabbits
Chemical Substances	Genetic Markers ; Ethanol (3K9958V90M) ; Cytochrome P-450 Enzyme System (9035-51-2) ; Cytochrome P-450 CYP2E1 (EC 1.14.13.-) ; Oxidoreductases, N-Demethylating (EC 1.5.-)
Language	English
Publishing date	1995-12
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	428999-7
ISSN	1530-0277 ; 0145-6008
ISSN (online)	1530-0277
ISSN	0145-6008
DOI	10.1111/j.1530-0277.1995.tb00994.x
Database	MEDical Literature Analysis and Retrieval System OnLINE

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