CYP2A6 polymorphisms: is there a role for pharmacogenomics in preventing coumarin-induced hepatotoxicity in lymphedema patients?
Identifieur interne : 007326 ( Main/Exploration ); précédent : 007325; suivant : 007327CYP2A6 polymorphisms: is there a role for pharmacogenomics in preventing coumarin-induced hepatotoxicity in lymphedema patients?
Auteurs : Nicholas Farinola [Australie] ; Neil B. PillerSource :
- Pharmacogenomics [ 1744-8042 ] ; 2007.
Descripteurs français
- KwdFr :
- MESH :
- effets indésirables : Coumarines.
- génétique : Lymphoedème, Maladies du foie, Polymorphisme génétique.
- traitement médicamenteux : Lymphoedème.
- Animaux, Humains, Lésions hépatiques dues aux substances, Maladies du foie, Pharmacogénétique.
English descriptors
- KwdEn :
- MESH :
- chemical , adverse effects : Coumarins.
- drug therapy : Lymphedema.
- genetics : Liver Diseases, Lymphedema, Polymorphism, Genetic.
- methods : Pharmacogenetics.
- prevention & control : Liver Diseases.
- Animals, Chemical and Drug Induced Liver Injury, Humans.
Abstract
Lymphedema is a chronic progressive and significantly disabling disease that affects over 150 million people worldwide. Coumarin is an effective pharmacological treatment, but is banned in some countries due to incidences of hepatotoxicity in rats and mice, and the rare finding of similar hepatotoxicity in humans. Cytochrome P450 (CYP)2A6 is the major enzyme involved in metabolizing coumarin to 7-hydroxycoumarin. A reduction in CYP2A6 activity will lead to shunting of coumarin into other metabolic pathways. In particular, coumarin is metabolized by CYP3A4 to form 3-hydroxycoumarin, the major metabolite in mice and rats. It has been shown that an increase in the 3-hydroxycoumarin ratio is associated with an increased production of the significant cytotoxic product o-hydroxyphenylacetylacetaldehyde (o-HPA), suggesting that a shunting of coumarin metabolism away from 7-hydroxylation is the cause of the toxicity. Hence, poor CYP2A6 metabolizers are more likely to metabolize coumarin via the cytotoxic pathway. Identifying these patients, and not treating them with coumarin, may reduce the incidence of toxicity associated with this drug. The technology to do so exists, but more information is required regarding the mechanism of coumarin toxicity.
DOI: 10.2217/14622416.8.2.151
PubMed: 17286538
Affiliations:
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Piller</name></author></analytic><series><title level="j">Pharmacogenomics</title><idno type="eISSN">1744-8042</idno><imprint><date when="2007" type="published">2007</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Chemical and Drug Induced Liver Injury</term><term>Coumarins (adverse effects)</term><term>Humans</term><term>Liver Diseases (genetics)</term><term>Liver Diseases (prevention & control)</term><term>Lymphedema (drug therapy)</term><term>Lymphedema (genetics)</term><term>Pharmacogenetics (methods)</term><term>Polymorphism, Genetic (genetics)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Coumarines (effets indésirables)</term><term>Humains</term><term>Lymphoedème (génétique)</term><term>Lymphoedème (traitement médicamenteux)</term><term>Lésions hépatiques dues aux substances</term><term>Maladies du foie ()</term><term>Maladies du foie (génétique)</term><term>Pharmacogénétique ()</term><term>Polymorphisme génétique (génétique)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="adverse effects" xml:lang="en"><term>Coumarins</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Lymphedema</term></keywords><keywords scheme="MESH" qualifier="effets indésirables" xml:lang="fr"><term>Coumarines</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Liver Diseases</term><term>Lymphedema</term><term>Polymorphism, Genetic</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Lymphoedème</term><term>Maladies du foie</term><term>Polymorphisme génétique</term></keywords><keywords scheme="MESH" qualifier="methods" xml:lang="en"><term>Pharmacogenetics</term></keywords><keywords scheme="MESH" qualifier="prevention & control" xml:lang="en"><term>Liver Diseases</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Lymphoedème</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Chemical and Drug Induced Liver Injury</term><term>Humans</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Humains</term><term>Lésions hépatiques dues aux substances</term><term>Maladies du foie</term><term>Pharmacogénétique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Lymphedema is a chronic progressive and significantly disabling disease that affects over 150 million people worldwide. Coumarin is an effective pharmacological treatment, but is banned in some countries due to incidences of hepatotoxicity in rats and mice, and the rare finding of similar hepatotoxicity in humans. Cytochrome P450 (CYP)2A6 is the major enzyme involved in metabolizing coumarin to 7-hydroxycoumarin. A reduction in CYP2A6 activity will lead to shunting of coumarin into other metabolic pathways. In particular, coumarin is metabolized by CYP3A4 to form 3-hydroxycoumarin, the major metabolite in mice and rats. It has been shown that an increase in the 3-hydroxycoumarin ratio is associated with an increased production of the significant cytotoxic product o-hydroxyphenylacetylacetaldehyde (o-HPA), suggesting that a shunting of coumarin metabolism away from 7-hydroxylation is the cause of the toxicity. Hence, poor CYP2A6 metabolizers are more likely to metabolize coumarin via the cytotoxic pathway. Identifying these patients, and not treating them with coumarin, may reduce the incidence of toxicity associated with this drug. The technology to do so exists, but more information is required regarding the mechanism of coumarin toxicity.</div></front></TEI><affiliations><list><country><li>Australie</li></country></list><tree><noCountry><name sortKey="Piller, Neil B" sort="Piller, Neil B" uniqKey="Piller N" first="Neil B" last="Piller">Neil B. Piller</name></noCountry><country name="Australie"><noRegion><name sortKey="Farinola, Nicholas" sort="Farinola, Nicholas" uniqKey="Farinola N" first="Nicholas" last="Farinola">Nicholas Farinola</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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