Hydroxylation of pregnenolone at the 7α- and 7β-positions by mouse liver microsomes. effects of cytochrome p450 inhibitors and structure-specific inhibition by steroid hormones
Identifieur interne : 004847 ( Main/Merge ); précédent : 004846; suivant : 004848Hydroxylation of pregnenolone at the 7α- and 7β-positions by mouse liver microsomes. effects of cytochrome p450 inhibitors and structure-specific inhibition by steroid hormones
Auteurs : Jaleh Doostzadeh [France] ; Anne-Cécile Cotillon [France] ; Robert Morfin [France]Source :
- Steroids [ 0039-128X ] ; 1998.
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Abstract
Hydroxylations of pregnenolone (PREG) at the 7α- and 7β- positions have been reported in numerous murine tissues and organs, including liver, and the responsible cytochrome P450 (P450) species await identification. Using thin-layer chromatography and gas chromatography–mass spectrometry and crystallization to constant specific activity, we report identification of 7α-hydroxy-PREG and 7β-hydroxy-PREG metabolites produced in mouse liver microsomes and kinetic studies of their production with apparent KM values of 2.45 ± 0.124 μM and 3.41 ± 0.236 μM for 7α- and 7β-hydroxylation, respectively. Investigation of P450 inhibitors and of steroid hormone effects on both 7α- and 7β-hydroxylation of PREG showed that 1) different P450 were involved because metyrapone and antipyrine inhibited solely 7α- and 7β-hydroxylation, respectively; 2) P450 1A2, 2D6, 2B1, and 2B11 were not responsible for 7α and 7β-hydroxylation of PREG because respective specific inhibitors furafylline, quinidine, and chloramphenicol triggered no inhibition; 3) P450 1A1 was responsible for only part of the 7β-hydroxylation of PREG because α-naphthoflavone, which inhibits specifically P450 1A1, did not suppress entirely 7β-hydroxylation while ketoconazole, antipyrine, and metyrapone extensively decreased the 7β-hydroxylation; 4) comparison of these findings with those obtained with brain microsomes suggests that tissue-specific P450 species are responsible for the 7α- and 7β-hydroxylation of PREG; and 5) 7α-hydroxylation of PREG may be shared with other 3β-hydroxysteroids such as isoandrosterone, 5-androstene-3β,17β-diol, and dehydroepiandrosterone, which acted in a competitive manner. Taken together, these findings will be of use for identification of the P450 species responsible for 7α- and 7β-hydroxylation of PREG and for studies of their activities in liver and other organs.
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DOI: 10.1016/S0039-128X(98)00012-9
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Hydroxylation of pregnenolone at the 7α- and 7β-positions by mouse liver microsomes. effects of cytochrome p450 inhibitors and structure-specific inhibition by steroid hormones</title><author><name sortKey="Doostzadeh, Jaleh" sort="Doostzadeh, Jaleh" uniqKey="Doostzadeh J" first="Jaleh" last="Doostzadeh">Jaleh Doostzadeh</name></author><author><name sortKey="Cotillon, Anne Cecile" sort="Cotillon, Anne Cecile" uniqKey="Cotillon A" first="Anne-Cécile" last="Cotillon">Anne-Cécile Cotillon</name></author><author><name sortKey="Morfin, Robert" sort="Morfin, Robert" uniqKey="Morfin R" first="Robert" last="Morfin">Robert Morfin</name></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:69BE5CF4B3527C6962C7239A2F38E779432C059A</idno><date when="1998" year="1998">1998</date><idno type="doi">10.1016/S0039-128X(98)00012-9</idno><idno type="url">https://api.istex.fr/document/69BE5CF4B3527C6962C7239A2F38E779432C059A/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">001D30</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">001D30</idno><idno type="wicri:Area/Istex/Curation">001D28</idno><idno type="wicri:Area/Istex/Checkpoint">001489</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Checkpoint">001489</idno><idno type="wicri:doubleKey">0039-128X:1998:Doostzadeh J:hydroxylation:of:pregnenolone</idno><idno type="wicri:Area/Main/Merge">004847</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Hydroxylation of pregnenolone at the 7α- and 7β-positions by mouse liver microsomes. effects of cytochrome p450 inhibitors and structure-specific inhibition by steroid hormones</title><author><name sortKey="Doostzadeh, Jaleh" sort="Doostzadeh, Jaleh" uniqKey="Doostzadeh J" first="Jaleh" last="Doostzadeh">Jaleh Doostzadeh</name><affiliation wicri:level="3"><country xml:lang="fr">France</country><wicri:regionArea>Laboratoire de Biotechnologie, Conservatoire National des Arts et Métiers, 2 rue Conté, 75141 Paris Cedex 03</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Cotillon, Anne Cecile" sort="Cotillon, Anne Cecile" uniqKey="Cotillon A" first="Anne-Cécile" last="Cotillon">Anne-Cécile Cotillon</name><affiliation wicri:level="3"><country xml:lang="fr">France</country><wicri:regionArea>Laboratoire de Biotechnologie, Conservatoire National des Arts et Métiers, 2 rue Conté, 75141 Paris Cedex 03</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Morfin, Robert" sort="Morfin, Robert" uniqKey="Morfin R" first="Robert" last="Morfin">Robert Morfin</name><affiliation wicri:level="1"><country wicri:rule="url">France</country></affiliation><affiliation wicri:level="3"><country xml:lang="fr">France</country><wicri:regionArea>Laboratoire de Biotechnologie, Conservatoire National des Arts et Métiers, 2 rue Conté, 75141 Paris Cedex 03</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author></analytic><monogr></monogr><series><title level="j">Steroids</title><title level="j" type="abbrev">STE</title><idno type="ISSN">0039-128X</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1998">1998</date><biblScope unit="volume">63</biblScope><biblScope unit="issue">7–8</biblScope><biblScope unit="page" from="383">383</biblScope><biblScope unit="page" to="392">392</biblScope></imprint><idno type="ISSN">0039-128X</idno></series><idno type="istex">69BE5CF4B3527C6962C7239A2F38E779432C059A</idno><idno type="DOI">10.1016/S0039-128X(98)00012-9</idno><idno type="PII">S0039-128X(98)00012-9</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0039-128X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>7-hydroxylation</term><term>cytochrome P450 inhibitor</term><term>inhibition</term><term>liver</term><term>mouse liver microsomes</term><term>pregnenolone</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Hydroxylations of pregnenolone (PREG) at the 7α- and 7β- positions have been reported in numerous murine tissues and organs, including liver, and the responsible cytochrome P450 (P450) species await identification. Using thin-layer chromatography and gas chromatography–mass spectrometry and crystallization to constant specific activity, we report identification of 7α-hydroxy-PREG and 7β-hydroxy-PREG metabolites produced in mouse liver microsomes and kinetic studies of their production with apparent KM values of 2.45 ± 0.124 μM and 3.41 ± 0.236 μM for 7α- and 7β-hydroxylation, respectively. Investigation of P450 inhibitors and of steroid hormone effects on both 7α- and 7β-hydroxylation of PREG showed that 1) different P450 were involved because metyrapone and antipyrine inhibited solely 7α- and 7β-hydroxylation, respectively; 2) P450 1A2, 2D6, 2B1, and 2B11 were not responsible for 7α and 7β-hydroxylation of PREG because respective specific inhibitors furafylline, quinidine, and chloramphenicol triggered no inhibition; 3) P450 1A1 was responsible for only part of the 7β-hydroxylation of PREG because α-naphthoflavone, which inhibits specifically P450 1A1, did not suppress entirely 7β-hydroxylation while ketoconazole, antipyrine, and metyrapone extensively decreased the 7β-hydroxylation; 4) comparison of these findings with those obtained with brain microsomes suggests that tissue-specific P450 species are responsible for the 7α- and 7β-hydroxylation of PREG; and 5) 7α-hydroxylation of PREG may be shared with other 3β-hydroxysteroids such as isoandrosterone, 5-androstene-3β,17β-diol, and dehydroepiandrosterone, which acted in a competitive manner. Taken together, these findings will be of use for identification of the P450 species responsible for 7α- and 7β-hydroxylation of PREG and for studies of their activities in liver and other organs.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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