Evaluation of rat hepatic 2E1 activity in function of age, sex and inducers: choice of an experimental model capable of testing the hepatotoxicity of low molecular weight compounds
Identifieur interne : 001D08 ( Istex/Corpus ); précédent : 001D07; suivant : 001D09Evaluation of rat hepatic 2E1 activity in function of age, sex and inducers: choice of an experimental model capable of testing the hepatotoxicity of low molecular weight compounds
Auteurs : G. Morel ; B. Cossec ; A. M. Lambert ; S. BinetSource :
- Toxicology Letters [ 0378-4274 ] ; 1999.
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Abstract
The aim of this work on rat hepatic P450 2E1 activity was to seek the most suitable experimental model to study the role of cytochrome P450 2E1 in the metabolism of industrial chemicals. Two sets of experiments were devoted to selecting the age and sex of animals and to estimating the response of male and female rats to different inducers. In the first set, the effect of three inducers (fasting; ethanol; acetone) was studied in male rats aged 5, 7 and 9 weeks. In the second set, the effect of different inducers, namely β-naphthoflavone (BNF), phenobarbital (PB), ethanol, acetone and pyridine, on PNP and chlorzoxazone (CLZO) hydroxylase activities was studied in 7 week old male and female rats. The results demonstrate firstly that microsomal p-nitrophenol (PNP) hydroxylase activity significantly decreases in control male rats in inverse function of age, and secondly that induction by ethanol decreases with age. The PNP hydroxylase activity level of controls and the significant increases in PNP hydroxylase activity observed in 7 week old male rats show that this is the most suitable age for the second set of experiments. In this second set, it was shown that P450 1A (induced by BNF) is involved in CLZO hydroxylase activity only. PB increased the hydroxylase activities in male and female rats by about 1.5 and 1.7 times those of the controls, respectively. The effects of P450 2E1 inducers in function of sex show that male rats exhibited more significant increases in PNP and CLZO hydroxylase activities than female. The specificity of these two substrates is discussed. Neither of these two reactions was specifically catalysed by P450 2E1, but PNP may be considered as the most specific and the least sensitive substrate. In addition, the linear relationship observed between the two substrates (PNP and CLZO) showed a good correlation between their activities (r=0.90, P<0.001). In conclusion, these results suggest the use of the 7 week old male rat as the experimental model to study the role of cytochrome P450 2E1 in the hepatotoxicity of low molecular weight industrial chemicals.
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DOI: 10.1016/S0378-4274(99)00058-2
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Lambert</name><affiliation><mods:affiliation>Institut National de Recherche et de Sécurité, Avenue de Bourgogne, B.P. No. 27, 54501 Vandoeuvre Cedex, France</mods:affiliation></affiliation></author><author><name sortKey="Binet, S" sort="Binet, S" uniqKey="Binet S" first="S." last="Binet">S. Binet</name><affiliation><mods:affiliation>Institut National de Recherche et de Sécurité, Avenue de Bourgogne, B.P. 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Morel</name><affiliation><mods:affiliation>Institut National de Recherche et de Sécurité, Avenue de Bourgogne, B.P. No. 27, 54501 Vandoeuvre Cedex, France</mods:affiliation></affiliation></author><author><name sortKey="Cossec, B" sort="Cossec, B" uniqKey="Cossec B" first="B." last="Cossec">B. Cossec</name><affiliation><mods:affiliation>Institut National de Recherche et de Sécurité, Avenue de Bourgogne, B.P. No. 27, 54501 Vandoeuvre Cedex, France</mods:affiliation></affiliation></author><author><name sortKey="Lambert, A M" sort="Lambert, A M" uniqKey="Lambert A" first="A. M." last="Lambert">A. M. Lambert</name><affiliation><mods:affiliation>Institut National de Recherche et de Sécurité, Avenue de Bourgogne, B.P. No. 27, 54501 Vandoeuvre Cedex, France</mods:affiliation></affiliation></author><author><name sortKey="Binet, S" sort="Binet, S" uniqKey="Binet S" first="S." last="Binet">S. Binet</name><affiliation><mods:affiliation>Institut National de Recherche et de Sécurité, Avenue de Bourgogne, B.P. No. 27, 54501 Vandoeuvre Cedex, France</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Toxicology Letters</title><title level="j" type="abbrev">TOXLET</title><idno type="ISSN">0378-4274</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1999">1999</date><biblScope unit="volume">106</biblScope><biblScope unit="issue">2–3</biblScope><biblScope unit="page" from="171">171</biblScope><biblScope unit="page" to="180">180</biblScope></imprint><idno type="ISSN">0378-4274</idno></series><idno type="istex">307CD97F3518A18CDFA0A408EFB04E1E7E2C97DA</idno><idno type="DOI">10.1016/S0378-4274(99)00058-2</idno><idno type="PII">S0378-4274(99)00058-2</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0378-4274</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Activity</term><term>Cytochrome P450 2E1</term><term>Inducers</term><term>Liver</term><term>Rat</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The aim of this work on rat hepatic P450 2E1 activity was to seek the most suitable experimental model to study the role of cytochrome P450 2E1 in the metabolism of industrial chemicals. Two sets of experiments were devoted to selecting the age and sex of animals and to estimating the response of male and female rats to different inducers. In the first set, the effect of three inducers (fasting; ethanol; acetone) was studied in male rats aged 5, 7 and 9 weeks. In the second set, the effect of different inducers, namely β-naphthoflavone (BNF), phenobarbital (PB), ethanol, acetone and pyridine, on PNP and chlorzoxazone (CLZO) hydroxylase activities was studied in 7 week old male and female rats. The results demonstrate firstly that microsomal p-nitrophenol (PNP) hydroxylase activity significantly decreases in control male rats in inverse function of age, and secondly that induction by ethanol decreases with age. The PNP hydroxylase activity level of controls and the significant increases in PNP hydroxylase activity observed in 7 week old male rats show that this is the most suitable age for the second set of experiments. In this second set, it was shown that P450 1A (induced by BNF) is involved in CLZO hydroxylase activity only. PB increased the hydroxylase activities in male and female rats by about 1.5 and 1.7 times those of the controls, respectively. The effects of P450 2E1 inducers in function of sex show that male rats exhibited more significant increases in PNP and CLZO hydroxylase activities than female. The specificity of these two substrates is discussed. Neither of these two reactions was specifically catalysed by P450 2E1, but PNP may be considered as the most specific and the least sensitive substrate. In addition, the linear relationship observed between the two substrates (PNP and CLZO) showed a good correlation between their activities (r=0.90, P<0.001). In conclusion, these results suggest the use of the 7 week old male rat as the experimental model to study the role of cytochrome P450 2E1 in the hepatotoxicity of low molecular weight industrial chemicals.</div></front></TEI><istex><corpusName>elsevier</corpusName><author><json:item><name>G. Morel</name><affiliations><json:string>Institut National de Recherche et de Sécurité, Avenue de Bourgogne, B.P. No. 27, 54501 Vandoeuvre Cedex, France</json:string></affiliations></json:item><json:item><name>B. Cossec</name><affiliations><json:string>Institut National de Recherche et de Sécurité, Avenue de Bourgogne, B.P. No. 27, 54501 Vandoeuvre Cedex, France</json:string></affiliations></json:item><json:item><name>A.M. Lambert</name><affiliations><json:string>Institut National de Recherche et de Sécurité, Avenue de Bourgogne, B.P. No. 27, 54501 Vandoeuvre Cedex, France</json:string></affiliations></json:item><json:item><name>S. Binet</name><affiliations><json:string>Institut National de Recherche et de Sécurité, Avenue de Bourgogne, B.P. No. 27, 54501 Vandoeuvre Cedex, France</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Activity</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Cytochrome P450 2E1</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Liver</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Rat</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Inducers</value></json:item></subject><language><json:string>eng</json:string></language><originalGenre><json:string>Short communication</json:string></originalGenre><abstract>The aim of this work on rat hepatic P450 2E1 activity was to seek the most suitable experimental model to study the role of cytochrome P450 2E1 in the metabolism of industrial chemicals. Two sets of experiments were devoted to selecting the age and sex of animals and to estimating the response of male and female rats to different inducers. In the first set, the effect of three inducers (fasting; ethanol; acetone) was studied in male rats aged 5, 7 and 9 weeks. In the second set, the effect of different inducers, namely β-naphthoflavone (BNF), phenobarbital (PB), ethanol, acetone and pyridine, on PNP and chlorzoxazone (CLZO) hydroxylase activities was studied in 7 week old male and female rats. The results demonstrate firstly that microsomal p-nitrophenol (PNP) hydroxylase activity significantly decreases in control male rats in inverse function of age, and secondly that induction by ethanol decreases with age. The PNP hydroxylase activity level of controls and the significant increases in PNP hydroxylase activity observed in 7 week old male rats show that this is the most suitable age for the second set of experiments. In this second set, it was shown that P450 1A (induced by BNF) is involved in CLZO hydroxylase activity only. PB increased the hydroxylase activities in male and female rats by about 1.5 and 1.7 times those of the controls, respectively. The effects of P450 2E1 inducers in function of sex show that male rats exhibited more significant increases in PNP and CLZO hydroxylase activities than female. The specificity of these two substrates is discussed. Neither of these two reactions was specifically catalysed by P450 2E1, but PNP may be considered as the most specific and the least sensitive substrate. In addition, the linear relationship observed between the two substrates (PNP and CLZO) showed a good correlation between their activities (r=0.90, P>0.001). In conclusion, these results suggest the use of the 7 week old male rat as the experimental model to study the role of cytochrome P450 2E1 in the hepatotoxicity of low molecular weight industrial chemicals.</abstract><qualityIndicators><score>8</score><pdfVersion>1.2</pdfVersion><pdfPageSize>535 x 675 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>5</keywordCount><abstractCharCount>2107</abstractCharCount><pdfWordCount>5075</pdfWordCount><pdfCharCount>30427</pdfCharCount><pdfPageCount>10</pdfPageCount><abstractWordCount>341</abstractWordCount></qualityIndicators><title>Evaluation of rat hepatic 2E1 activity in function of age, sex and inducers: choice of an experimental model capable of testing the hepatotoxicity of low molecular weight compounds</title><pii><json:string>S0378-4274(99)00058-2</json:string></pii><refBibs><json:item><author><json:item><name>B.L. Brown</name></json:item><json:item><name>J.W. Allis</name></json:item><json:item><name>J.E. 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Res.</title></host><title>Effect of pyrazole and dexamethasone administration on cytochrome P450 2E1 and 3A isoforms in rat liver and kidney: lack of specificity of p-nitrophenol as a substrate of P450 2E1</title></json:item></refBibs><genre><json:string>brief-communication</json:string></genre><host><volume>106</volume><pii><json:string>S0378-4274(00)X0056-2</json:string></pii><pages><last>180</last><first>171</first></pages><issn><json:string>0378-4274</json:string></issn><issue>2–3</issue><genre><json:string>journal</json:string></genre><language><json:string>unknown</json:string></language><title>Toxicology Letters</title><publicationDate>1999</publicationDate></host><categories><wos><json:string>science</json:string><json:string>toxicology</json:string></wos><scienceMetrix><json:string>health sciences</json:string><json:string>biomedical research</json:string><json:string>toxicology</json:string></scienceMetrix></categories><publicationDate>1999</publicationDate><copyrightDate>1999</copyrightDate><doi><json:string>10.1016/S0378-4274(99)00058-2</json:string></doi><id>307CD97F3518A18CDFA0A408EFB04E1E7E2C97DA</id><score>0.14105816</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/307CD97F3518A18CDFA0A408EFB04E1E7E2C97DA/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/document/307CD97F3518A18CDFA0A408EFB04E1E7E2C97DA/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/307CD97F3518A18CDFA0A408EFB04E1E7E2C97DA/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Evaluation of rat hepatic 2E1 activity in function of age, sex and inducers: choice of an experimental model capable of testing the hepatotoxicity of low molecular weight compounds</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>ELSEVIER</publisher><availability><p>©1999 Elsevier Science Ireland Ltd</p></availability><date>1999</date></publicationStmt><notesStmt><note type="content">Fig. 1: Effect of the age of male rats on microsomal p-nitrophenol hydroxylase activity induced by one day of fasting, acetone (5ml/kg of 25% solution) injected by single gavage (24 h before sacrifice), and ethanol (15% in drinking water) for 6 days. Data represent means±S.E. of five rats per group. The comparison between control and treated groups was made using one way analysis of variance, followed by Student–Neuwman–Keuls test. Significantly different from control group: *P=0.05; **P=0.01. The comparison between the three control groups was made using the same test. Significantly different from control group aged 5 weeks: +P<0.01.</note><note type="content">Fig. 3: Correlation analysis between microsomal hydroxylase activities for p-nitrophenol and chlorzoxazone as substrates. Microsomes from control, fasted, acetone, ethanol, phenobarbital and pyridine male and female rats were used (n=92).</note><note type="content">Fig. 2: Double reciprocal plots. Chlorzoxazone hydroxylase activity was assayed using microsomes from control rat liver (0.4 mg/ml incubation). A chlorzoxazone concentration range from 0.04 to 0.8 mM was used. Points were means and S.D. of three determinations. Kinetic parameters were determined by linear regression analysis: • Km=75 μM and Vm=1.10 nmol/mg min; ΔKm=253 μM and Vm=1.64 nmol/mg min.</note><note type="content">Table 1: Effect of various inducers on microsomal p-nitrophenol and chlorzoxazone hydroxylase activities in the male rata</note><note type="content">Table 2: Effect of various inducers on microsomal p-nitrophenol and chlorzoxazone hydroxylase activities in the female rata</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Evaluation of rat hepatic 2E1 activity in function of age, sex and inducers: choice of an experimental model capable of testing the hepatotoxicity of low molecular weight compounds</title><author xml:id="author-1"><persName><forename type="first">G.</forename><surname>Morel</surname></persName><note type="correspondence"><p>Corresponding author. Tel.: +33-383502000; fax: +33-383502096</p></note><affiliation>Institut National de Recherche et de Sécurité, Avenue de Bourgogne, B.P. No. 27, 54501 Vandoeuvre Cedex, France</affiliation></author><author xml:id="author-2"><persName><forename type="first">B.</forename><surname>Cossec</surname></persName><affiliation>Institut National de Recherche et de Sécurité, Avenue de Bourgogne, B.P. No. 27, 54501 Vandoeuvre Cedex, France</affiliation></author><author xml:id="author-3"><persName><forename type="first">A.M.</forename><surname>Lambert</surname></persName><affiliation>Institut National de Recherche et de Sécurité, Avenue de Bourgogne, B.P. No. 27, 54501 Vandoeuvre Cedex, France</affiliation></author><author xml:id="author-4"><persName><forename type="first">S.</forename><surname>Binet</surname></persName><affiliation>Institut National de Recherche et de Sécurité, Avenue de Bourgogne, B.P. No. 27, 54501 Vandoeuvre Cedex, France</affiliation></author></analytic><monogr><title level="j">Toxicology Letters</title><title level="j" type="abbrev">TOXLET</title><idno type="pISSN">0378-4274</idno><idno type="PII">S0378-4274(00)X0056-2</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1999"></date><biblScope unit="volume">106</biblScope><biblScope unit="issue">2–3</biblScope><biblScope unit="page" from="171">171</biblScope><biblScope unit="page" to="180">180</biblScope></imprint></monogr><idno type="istex">307CD97F3518A18CDFA0A408EFB04E1E7E2C97DA</idno><idno type="DOI">10.1016/S0378-4274(99)00058-2</idno><idno type="PII">S0378-4274(99)00058-2</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>1999</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>The aim of this work on rat hepatic P450 2E1 activity was to seek the most suitable experimental model to study the role of cytochrome P450 2E1 in the metabolism of industrial chemicals. Two sets of experiments were devoted to selecting the age and sex of animals and to estimating the response of male and female rats to different inducers. In the first set, the effect of three inducers (fasting; ethanol; acetone) was studied in male rats aged 5, 7 and 9 weeks. In the second set, the effect of different inducers, namely β-naphthoflavone (BNF), phenobarbital (PB), ethanol, acetone and pyridine, on PNP and chlorzoxazone (CLZO) hydroxylase activities was studied in 7 week old male and female rats. The results demonstrate firstly that microsomal p-nitrophenol (PNP) hydroxylase activity significantly decreases in control male rats in inverse function of age, and secondly that induction by ethanol decreases with age. The PNP hydroxylase activity level of controls and the significant increases in PNP hydroxylase activity observed in 7 week old male rats show that this is the most suitable age for the second set of experiments. In this second set, it was shown that P450 1A (induced by BNF) is involved in CLZO hydroxylase activity only. PB increased the hydroxylase activities in male and female rats by about 1.5 and 1.7 times those of the controls, respectively. The effects of P450 2E1 inducers in function of sex show that male rats exhibited more significant increases in PNP and CLZO hydroxylase activities than female. The specificity of these two substrates is discussed. Neither of these two reactions was specifically catalysed by P450 2E1, but PNP may be considered as the most specific and the least sensitive substrate. In addition, the linear relationship observed between the two substrates (PNP and CLZO) showed a good correlation between their activities (r=0.90, P<0.001). In conclusion, these results suggest the use of the 7 week old male rat as the experimental model to study the role of cytochrome P450 2E1 in the hepatotoxicity of low molecular weight industrial chemicals.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>Activity</term></item><item><term>Cytochrome P450 2E1</term></item><item><term>Liver</term></item><item><term>Rat</term></item><item><term>Inducers</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="1999-02-22">Modified</change><change when="1999">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/307CD97F3518A18CDFA0A408EFB04E1E7E2C97DA/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Elsevier, elements deleted: ce:floats; body; tail"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//ES//DTD journal article DTD version 4.5.2//EN//XML" URI="art452.dtd" name="istex:docType"><istex:entity SYSTEM="gr1" NDATA="IMAGE" name="gr1"></istex:entity><istex:entity SYSTEM="gr3" NDATA="IMAGE" name="gr3"></istex:entity><istex:entity SYSTEM="gr2" NDATA="IMAGE" name="gr2"></istex:entity></istex:docType><istex:document><converted-article version="4.5.2" docsubtype="sco" xml:lang="en"><item-info><jid>TOXLET</jid><aid>4410</aid><ce:pii>S0378-4274(99)00058-2</ce:pii><ce:doi>10.1016/S0378-4274(99)00058-2</ce:doi><ce:copyright type="full-transfer" year="1999">Elsevier Science Ireland Ltd</ce:copyright></item-info><head><ce:title>Evaluation of rat hepatic 2E1 activity in function of age, sex and inducers: choice of an experimental model capable of testing the hepatotoxicity of low molecular weight compounds</ce:title><ce:author-group><ce:author><ce:given-name>G.</ce:given-name><ce:surname>Morel</ce:surname><ce:cross-ref refid="COR1">*</ce:cross-ref></ce:author><ce:author><ce:given-name>B.</ce:given-name><ce:surname>Cossec</ce:surname></ce:author><ce:author><ce:given-name>A.M.</ce:given-name><ce:surname>Lambert</ce:surname></ce:author><ce:author><ce:given-name>S.</ce:given-name><ce:surname>Binet</ce:surname></ce:author><ce:affiliation><ce:textfn>Institut National de Recherche et de Sécurité, Avenue de Bourgogne, B.P. No. 27, 54501 Vandoeuvre Cedex, France</ce:textfn></ce:affiliation><ce:correspondence id="COR1"><ce:label>*</ce:label><ce:text>Corresponding author. Tel.: +33-383502000; fax: +33-383502096</ce:text></ce:correspondence></ce:author-group><ce:date-received day="25" month="11" year="1998"></ce:date-received><ce:date-revised day="22" month="2" year="1999"></ce:date-revised><ce:date-accepted day="26" month="2" year="1999"></ce:date-accepted><ce:abstract><ce:section-title>Abstract</ce:section-title><ce:abstract-sec><ce:simple-para>The aim of this work on rat hepatic P450 2E1 activity was to seek the most suitable experimental model to study the role of cytochrome P450 2E1 in the metabolism of industrial chemicals. Two sets of experiments were devoted to selecting the age and sex of animals and to estimating the response of male and female rats to different inducers. In the first set, the effect of three inducers (fasting; ethanol; acetone) was studied in male rats aged 5, 7 and 9 weeks. In the second set, the effect of different inducers, namely β-naphthoflavone (BNF), phenobarbital (PB), ethanol, acetone and pyridine, on PNP and chlorzoxazone (CLZO) hydroxylase activities was studied in 7 week old male and female rats. The results demonstrate firstly that microsomal <ce:italic>p</ce:italic>-nitrophenol (PNP) hydroxylase activity significantly decreases in control male rats in inverse function of age, and secondly that induction by ethanol decreases with age. The PNP hydroxylase activity level of controls and the significant increases in PNP hydroxylase activity observed in 7 week old male rats show that this is the most suitable age for the second set of experiments. In this second set, it was shown that P450 1A (induced by BNF) is involved in CLZO hydroxylase activity only. PB increased the hydroxylase activities in male and female rats by about 1.5 and 1.7 times those of the controls, respectively. The effects of P450 2E1 inducers in function of sex show that male rats exhibited more significant increases in PNP and CLZO hydroxylase activities than female. The specificity of these two substrates is discussed. Neither of these two reactions was specifically catalysed by P450 2E1, but PNP may be considered as the most specific and the least sensitive substrate. In addition, the linear relationship observed between the two substrates (PNP and CLZO) showed a good correlation between their activities (<ce:italic>r</ce:italic>=0.90, <ce:italic>P</ce:italic><0.001). In conclusion, these results suggest the use of the 7 week old male rat as the experimental model to study the role of cytochrome P450 2E1 in the hepatotoxicity of low molecular weight industrial chemicals.</ce:simple-para></ce:abstract-sec></ce:abstract><ce:keywords class="keyword"><ce:section-title>Keywords</ce:section-title><ce:keyword><ce:text>Activity</ce:text></ce:keyword><ce:keyword><ce:text>Cytochrome P450 2E1</ce:text></ce:keyword><ce:keyword><ce:text>Liver</ce:text></ce:keyword><ce:keyword><ce:text>Rat</ce:text></ce:keyword><ce:keyword><ce:text>Inducers</ce:text></ce:keyword></ce:keywords></head></converted-article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Evaluation of rat hepatic 2E1 activity in function of age, sex and inducers: choice of an experimental model capable of testing the hepatotoxicity of low molecular weight compounds</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>Evaluation of rat hepatic 2E1 activity in function of age, sex and inducers: choice of an experimental model capable of testing the hepatotoxicity of low molecular weight compounds</title></titleInfo><name type="personal"><namePart type="given">G.</namePart><namePart type="family">Morel</namePart><affiliation>Institut National de Recherche et de Sécurité, Avenue de Bourgogne, B.P. No. 27, 54501 Vandoeuvre Cedex, France</affiliation><description>Corresponding author. Tel.: +33-383502000; fax: +33-383502096</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">B.</namePart><namePart type="family">Cossec</namePart><affiliation>Institut National de Recherche et de Sécurité, Avenue de Bourgogne, B.P. No. 27, 54501 Vandoeuvre Cedex, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">A.M.</namePart><namePart type="family">Lambert</namePart><affiliation>Institut National de Recherche et de Sécurité, Avenue de Bourgogne, B.P. No. 27, 54501 Vandoeuvre Cedex, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">S.</namePart><namePart type="family">Binet</namePart><affiliation>Institut National de Recherche et de Sécurité, Avenue de Bourgogne, B.P. No. 27, 54501 Vandoeuvre Cedex, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="brief-communication" displayLabel="Short communication"></genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">1999</dateIssued><dateModified encoding="w3cdtf">1999-02-22</dateModified><copyrightDate encoding="w3cdtf">1999</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract lang="en">The aim of this work on rat hepatic P450 2E1 activity was to seek the most suitable experimental model to study the role of cytochrome P450 2E1 in the metabolism of industrial chemicals. Two sets of experiments were devoted to selecting the age and sex of animals and to estimating the response of male and female rats to different inducers. In the first set, the effect of three inducers (fasting; ethanol; acetone) was studied in male rats aged 5, 7 and 9 weeks. In the second set, the effect of different inducers, namely β-naphthoflavone (BNF), phenobarbital (PB), ethanol, acetone and pyridine, on PNP and chlorzoxazone (CLZO) hydroxylase activities was studied in 7 week old male and female rats. The results demonstrate firstly that microsomal p-nitrophenol (PNP) hydroxylase activity significantly decreases in control male rats in inverse function of age, and secondly that induction by ethanol decreases with age. The PNP hydroxylase activity level of controls and the significant increases in PNP hydroxylase activity observed in 7 week old male rats show that this is the most suitable age for the second set of experiments. In this second set, it was shown that P450 1A (induced by BNF) is involved in CLZO hydroxylase activity only. PB increased the hydroxylase activities in male and female rats by about 1.5 and 1.7 times those of the controls, respectively. The effects of P450 2E1 inducers in function of sex show that male rats exhibited more significant increases in PNP and CLZO hydroxylase activities than female. The specificity of these two substrates is discussed. Neither of these two reactions was specifically catalysed by P450 2E1, but PNP may be considered as the most specific and the least sensitive substrate. In addition, the linear relationship observed between the two substrates (PNP and CLZO) showed a good correlation between their activities (r=0.90, P<0.001). In conclusion, these results suggest the use of the 7 week old male rat as the experimental model to study the role of cytochrome P450 2E1 in the hepatotoxicity of low molecular weight industrial chemicals.</abstract><note type="content">Fig. 1: Effect of the age of male rats on microsomal p-nitrophenol hydroxylase activity induced by one day of fasting, acetone (5ml/kg of 25% solution) injected by single gavage (24 h before sacrifice), and ethanol (15% in drinking water) for 6 days. Data represent means±S.E. of five rats per group. The comparison between control and treated groups was made using one way analysis of variance, followed by Student–Neuwman–Keuls test. Significantly different from control group: *P=0.05; **P=0.01. The comparison between the three control groups was made using the same test. Significantly different from control group aged 5 weeks: +P<0.01.</note><note type="content">Fig. 3: Correlation analysis between microsomal hydroxylase activities for p-nitrophenol and chlorzoxazone as substrates. Microsomes from control, fasted, acetone, ethanol, phenobarbital and pyridine male and female rats were used (n=92).</note><note type="content">Fig. 2: Double reciprocal plots. Chlorzoxazone hydroxylase activity was assayed using microsomes from control rat liver (0.4 mg/ml incubation). A chlorzoxazone concentration range from 0.04 to 0.8 mM was used. Points were means and S.D. of three determinations. Kinetic parameters were determined by linear regression analysis: • Km=75 μM and Vm=1.10 nmol/mg min; ΔKm=253 μM and Vm=1.64 nmol/mg min.</note><note type="content">Table 1: Effect of various inducers on microsomal p-nitrophenol and chlorzoxazone hydroxylase activities in the male rata</note><note type="content">Table 2: Effect of various inducers on microsomal p-nitrophenol and chlorzoxazone hydroxylase activities in the female rata</note><subject lang="en"><genre>Keywords</genre><topic>Activity</topic><topic>Cytochrome P450 2E1</topic><topic>Liver</topic><topic>Rat</topic><topic>Inducers</topic></subject><relatedItem type="host"><titleInfo><title>Toxicology Letters</title></titleInfo><titleInfo type="abbreviated"><title>TOXLET</title></titleInfo><genre type="journal">journal</genre><originInfo><dateIssued encoding="w3cdtf">19990601</dateIssued></originInfo><identifier type="ISSN">0378-4274</identifier><identifier type="PII">S0378-4274(00)X0056-2</identifier><part><date>19990601</date><detail type="volume"><number>106</number><caption>vol.</caption></detail><detail type="issue"><number>2–3</number><caption>no.</caption></detail><extent unit="issue pages"><start>89</start><end>262</end></extent><extent unit="pages"><start>171</start><end>180</end></extent></part></relatedItem><identifier type="istex">307CD97F3518A18CDFA0A408EFB04E1E7E2C97DA</identifier><identifier type="DOI">10.1016/S0378-4274(99)00058-2</identifier><identifier type="PII">S0378-4274(99)00058-2</identifier><accessCondition type="use and reproduction" contentType="copyright">©1999 Elsevier Science Ireland Ltd</accessCondition><recordInfo><recordContentSource>ELSEVIER</recordContentSource><recordOrigin>Elsevier Science Ireland Ltd, ©1999</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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