Role of CYP2B6 and CYP3A4 in the in vitro N-dechloroethylation of (R)- and (S)-ifosfamide in human liver microsomes.
Identifieur interne : 003607 ( Main/Exploration ); précédent : 003606; suivant : 003608Role of CYP2B6 and CYP3A4 in the in vitro N-dechloroethylation of (R)- and (S)-ifosfamide in human liver microsomes.
Auteurs : C P Granvil [Canada] ; A. Madan ; M. Sharkawi ; A. Parkinson ; I W WainerSource :
- Drug metabolism and disposition: the biological fate of chemicals [ 0090-9556 ] ; 1999.
English descriptors
- KwdEn :
- Animals, Antineoplastic Agents, Alkylating (metabolism), Antineoplastic Agents, Alkylating (pharmacokinetics), Antineoplastic Agents, Alkylating (toxicity), Aryl Hydrocarbon Hydroxylases, Biotransformation, Cytochrome P-450 CYP2B6, Cytochrome P-450 CYP3A, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Enzyme System (genetics), Cytochrome P-450 Enzyme System (immunology), Cytochrome P-450 Enzyme System (metabolism), DNA, Complementary (biosynthesis), Humans, Ifosfamide (metabolism), Ifosfamide (pharmacokinetics), Ifosfamide (toxicity), Isoenzymes (antagonists & inhibitors), Isoenzymes (genetics), Isoenzymes (immunology), Isoenzymes (metabolism), Kinetics, Male, Microsomes, Liver (enzymology), Microsomes, Liver (metabolism), Mixed Function Oxygenases (antagonists & inhibitors), Mixed Function Oxygenases (genetics), Mixed Function Oxygenases (immunology), Mixed Function Oxygenases (metabolism), Oxidoreductases, N-Demethylating (antagonists & inhibitors), Oxidoreductases, N-Demethylating (genetics), Oxidoreductases, N-Demethylating (metabolism), Rabbits, Rats, Stereoisomerism, Substrate Specificity, Transfection.
- MESH :
- chemical , antagonists & inhibitors : Isoenzymes, Mixed Function Oxygenases, Oxidoreductases, N-Demethylating.
- chemical , biosynthesis : DNA, Complementary.
- chemical , genetics : Cytochrome P-450 Enzyme System, Isoenzymes, Mixed Function Oxygenases, Oxidoreductases, N-Demethylating.
- chemical , immunology : Cytochrome P-450 Enzyme System, Isoenzymes, Mixed Function Oxygenases.
- chemical , metabolism : Antineoplastic Agents, Alkylating, Cytochrome P-450 Enzyme System, Ifosfamide, Isoenzymes, Mixed Function Oxygenases, Oxidoreductases, N-Demethylating.
- chemical , pharmacokinetics : Antineoplastic Agents, Alkylating, Ifosfamide.
- chemical , toxicity : Antineoplastic Agents, Alkylating, Ifosfamide.
- enzymology : Microsomes, Liver.
- metabolism : Microsomes, Liver.
- Animals, Aryl Hydrocarbon Hydroxylases, Biotransformation, Cytochrome P-450 CYP2B6, Cytochrome P-450 CYP3A, Cytochrome P-450 Enzyme Inhibitors, Humans, Kinetics, Male, Rabbits, Rats, Stereoisomerism, Substrate Specificity, Transfection.
Abstract
The central nervous system toxicity of ifosfamide (IFF), a chiral antineoplastic agent, is thought to be dependent on its N-dechloroethylation by hepatic cytochrome P-450 (CYP) enzymes. The purpose of this study was to identify the human CYPs responsible for IFF-N-dechloroethylation and their corresponding regio- and enantioselectivities. IFF exists in two enantiomeric forms, (R) - and (S)-IFF, which can be dechloroethylated at either the N2 or N3 positions, producing the corresponding (R,S)-2-dechloroethyl-IFF [(R, S)-2-DCE-IFF] and (R,S)-3-dechloroethyl-IFF [(R,S)-3-DCE-IFF]. The results of the present study suggest that the production of (R)-2-DCE-IFF and (S)-3-DCE-IFF from (R)-IFF is catalyzed by different CYPs as is the production of (S)-2-DCE-IFF and (R)-3-DCE-IFF from (S)-IFF. In vitro studies with a bank of human liver microsomes revealed that the sample-to-sample variation in the production of (S)-3-DCE-IFF from (R)-IFF and (S)-2-DCE-IFF from (S)-IFF was highly correlated with the levels of (S)-mephenytoin N-demethylation (CYP2B6), whereas (R)-2-DCE-IFF production from (R)-IFF and (R)-3-DCE-IFF production from (S)-IFF were both correlated with the activity of testosterone 6beta-hydroxylation (CYP3A4/5). Experiments with cDNA-expressed P-450 and antibody and chemical inhibition studies supported the conclusion that the formation of (S)-3-DCE-IFF and (S)-2-DCE-IFF is catalyzed primarily by CYP2B6, whereas (R)-2-DCE-IFF and (R)-3-DCE-IFF are primarily the result of CYP3A4/5 activity.
PubMed: 10101149
Affiliations:
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Le document en format XML
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Sharkawi</name></author><author><name sortKey="Parkinson, A" sort="Parkinson, A" uniqKey="Parkinson A" first="A" last="Parkinson">A. Parkinson</name></author><author><name sortKey="Wainer, I W" sort="Wainer, I W" uniqKey="Wainer I" first="I W" last="Wainer">I W Wainer</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="1999">1999</date><idno type="RBID">pubmed:10101149</idno><idno type="pmid">10101149</idno><idno type="wicri:Area/PubMed/Corpus">001717</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001717</idno><idno type="wicri:Area/PubMed/Curation">001717</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">001717</idno><idno type="wicri:Area/PubMed/Checkpoint">001717</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">001717</idno><idno type="wicri:Area/Ncbi/Merge">000009</idno><idno type="wicri:Area/Ncbi/Curation">000009</idno><idno type="wicri:Area/Ncbi/Checkpoint">000009</idno><idno type="wicri:doubleKey">0090-9556:1999:Granvil C:role:of:cyp</idno><idno type="wicri:Area/Main/Merge">003B62</idno><idno type="wicri:Area/Main/Curation">003607</idno><idno type="wicri:Area/Main/Exploration">003607</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Role of CYP2B6 and CYP3A4 in the in vitro N-dechloroethylation of (R)- and (S)-ifosfamide in human liver microsomes.</title><author><name sortKey="Granvil, C P" sort="Granvil, C P" uniqKey="Granvil C" first="C P" last="Granvil">C P Granvil</name><affiliation wicri:level="1"><nlm:affiliation>Département de Pharmacologie, Université de Montréal, Montréal, Québec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Département de Pharmacologie, Université de Montréal, Montréal, Québec</wicri:regionArea><wicri:noRegion>Québec</wicri:noRegion></affiliation></author><author><name sortKey="Madan, A" sort="Madan, A" uniqKey="Madan A" first="A" last="Madan">A. Madan</name></author><author><name sortKey="Sharkawi, M" sort="Sharkawi, M" uniqKey="Sharkawi M" first="M" last="Sharkawi">M. Sharkawi</name></author><author><name sortKey="Parkinson, A" sort="Parkinson, A" uniqKey="Parkinson A" first="A" last="Parkinson">A. Parkinson</name></author><author><name sortKey="Wainer, I W" sort="Wainer, I W" uniqKey="Wainer I" first="I W" last="Wainer">I W Wainer</name></author></analytic><series><title level="j">Drug metabolism and disposition: the biological fate of chemicals</title><idno type="ISSN">0090-9556</idno><imprint><date when="1999" type="published">1999</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Antineoplastic Agents, Alkylating (metabolism)</term><term>Antineoplastic Agents, Alkylating (pharmacokinetics)</term><term>Antineoplastic Agents, Alkylating (toxicity)</term><term>Aryl Hydrocarbon Hydroxylases</term><term>Biotransformation</term><term>Cytochrome P-450 CYP2B6</term><term>Cytochrome P-450 CYP3A</term><term>Cytochrome P-450 Enzyme Inhibitors</term><term>Cytochrome P-450 Enzyme System (genetics)</term><term>Cytochrome P-450 Enzyme System (immunology)</term><term>Cytochrome P-450 Enzyme System (metabolism)</term><term>DNA, Complementary (biosynthesis)</term><term>Humans</term><term>Ifosfamide (metabolism)</term><term>Ifosfamide (pharmacokinetics)</term><term>Ifosfamide (toxicity)</term><term>Isoenzymes (antagonists & inhibitors)</term><term>Isoenzymes (genetics)</term><term>Isoenzymes (immunology)</term><term>Isoenzymes (metabolism)</term><term>Kinetics</term><term>Male</term><term>Microsomes, Liver (enzymology)</term><term>Microsomes, Liver (metabolism)</term><term>Mixed Function Oxygenases (antagonists & inhibitors)</term><term>Mixed Function Oxygenases (genetics)</term><term>Mixed Function Oxygenases (immunology)</term><term>Mixed Function Oxygenases (metabolism)</term><term>Oxidoreductases, N-Demethylating (antagonists & inhibitors)</term><term>Oxidoreductases, N-Demethylating (genetics)</term><term>Oxidoreductases, N-Demethylating (metabolism)</term><term>Rabbits</term><term>Rats</term><term>Stereoisomerism</term><term>Substrate Specificity</term><term>Transfection</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Isoenzymes</term><term>Mixed Function Oxygenases</term><term>Oxidoreductases, N-Demethylating</term></keywords><keywords scheme="MESH" type="chemical" qualifier="biosynthesis" xml:lang="en"><term>DNA, Complementary</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Cytochrome P-450 Enzyme System</term><term>Isoenzymes</term><term>Mixed Function Oxygenases</term><term>Oxidoreductases, N-Demethylating</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Cytochrome P-450 Enzyme System</term><term>Isoenzymes</term><term>Mixed Function Oxygenases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Antineoplastic Agents, Alkylating</term><term>Cytochrome P-450 Enzyme System</term><term>Ifosfamide</term><term>Isoenzymes</term><term>Mixed Function Oxygenases</term><term>Oxidoreductases, N-Demethylating</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacokinetics" xml:lang="en"><term>Antineoplastic Agents, Alkylating</term><term>Ifosfamide</term></keywords><keywords scheme="MESH" type="chemical" qualifier="toxicity" xml:lang="en"><term>Antineoplastic Agents, Alkylating</term><term>Ifosfamide</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Microsomes, Liver</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Microsomes, Liver</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Aryl Hydrocarbon Hydroxylases</term><term>Biotransformation</term><term>Cytochrome P-450 CYP2B6</term><term>Cytochrome P-450 CYP3A</term><term>Cytochrome P-450 Enzyme Inhibitors</term><term>Humans</term><term>Kinetics</term><term>Male</term><term>Rabbits</term><term>Rats</term><term>Stereoisomerism</term><term>Substrate Specificity</term><term>Transfection</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The central nervous system toxicity of ifosfamide (IFF), a chiral antineoplastic agent, is thought to be dependent on its N-dechloroethylation by hepatic cytochrome P-450 (CYP) enzymes. The purpose of this study was to identify the human CYPs responsible for IFF-N-dechloroethylation and their corresponding regio- and enantioselectivities. IFF exists in two enantiomeric forms, (R) - and (S)-IFF, which can be dechloroethylated at either the N2 or N3 positions, producing the corresponding (R,S)-2-dechloroethyl-IFF [(R, S)-2-DCE-IFF] and (R,S)-3-dechloroethyl-IFF [(R,S)-3-DCE-IFF]. The results of the present study suggest that the production of (R)-2-DCE-IFF and (S)-3-DCE-IFF from (R)-IFF is catalyzed by different CYPs as is the production of (S)-2-DCE-IFF and (R)-3-DCE-IFF from (S)-IFF. In vitro studies with a bank of human liver microsomes revealed that the sample-to-sample variation in the production of (S)-3-DCE-IFF from (R)-IFF and (S)-2-DCE-IFF from (S)-IFF was highly correlated with the levels of (S)-mephenytoin N-demethylation (CYP2B6), whereas (R)-2-DCE-IFF production from (R)-IFF and (R)-3-DCE-IFF production from (S)-IFF were both correlated with the activity of testosterone 6beta-hydroxylation (CYP3A4/5). Experiments with cDNA-expressed P-450 and antibody and chemical inhibition studies supported the conclusion that the formation of (S)-3-DCE-IFF and (S)-2-DCE-IFF is catalyzed primarily by CYP2B6, whereas (R)-2-DCE-IFF and (R)-3-DCE-IFF are primarily the result of CYP3A4/5 activity.</div></front></TEI><affiliations><list><country><li>Canada</li></country></list><tree><noCountry><name sortKey="Madan, A" sort="Madan, A" uniqKey="Madan A" first="A" last="Madan">A. Madan</name><name sortKey="Parkinson, A" sort="Parkinson, A" uniqKey="Parkinson A" first="A" last="Parkinson">A. Parkinson</name><name sortKey="Sharkawi, M" sort="Sharkawi, M" uniqKey="Sharkawi M" first="M" last="Sharkawi">M. Sharkawi</name><name sortKey="Wainer, I W" sort="Wainer, I W" uniqKey="Wainer I" first="I W" last="Wainer">I W Wainer</name></noCountry><country name="Canada"><noRegion><name sortKey="Granvil, C P" sort="Granvil, C P" uniqKey="Granvil C" first="C P" last="Granvil">C P Granvil</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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