A single amino acid substitution (Leu160His) in cytochrome P 450 CYP2A6 causes switching from 7-hydroxylation to 3-hydroxylation of coumarin
Identifieur interne : 000A68 ( Istex/Curation ); précédent : 000A67; suivant : 000A69A single amino acid substitution (Leu160His) in cytochrome P 450 CYP2A6 causes switching from 7-hydroxylation to 3-hydroxylation of coumarin
Auteurs : H. Hadidi [Norvège, Jordanie] ; K. Zahlsen [Norvège] ; J. R. Idle [Norvège] ; S. Cholerton [Royaume-Uni]Source :
- Food and Chemical Toxicology [ 0278-6915 ] ; 1997.
Abstract
Human populations are thought to metabolize coumarin almost exclusively by 7-hydroxylation. We have identified an individual who is homozygous for a single amino acid substitution (Leul60His) in the cytochrome P450 CYP2A6 arising from the variant CYP2A6∗2 allele. On administration of coumarin (2 mg orally) no detectable 7-hydroxycoumarin was excreted in the 0–8-hr urine, rather, approximately 50% of the dose was eliminated as 2-hydroxyphenylacetic acid, the end-product of coumarin 3-hydroxylation. His immediate family members, who were heterozygous for the CYP2A6∗2 allele, excreted little 2-hydroxyphenylacetic acid and mainly 7-hydroxycoumarin, when similarly tested. These findings raise a question regarding human risk evaluations for environmental coumarin exposures, since 7-hydroxylation is regarded as a detoxication pathway, but 3-hydroxylation as the process required to lead to macromolecular covalent binding of coumarin. Persons homozygous for the CYP2A6∗2 allele may constitute 1–25% of various populations.
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DOI: 10.1016/S0278-6915(97)00066-5
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Hadidi</name><affiliation wicri:level="1"><mods:affiliation>Institute for Cancer Research and Molecular Biology, Norwegian University of Science and Technology, 7005 Trondheim, Norway</mods:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Institute for Cancer Research and Molecular Biology, Norwegian University of Science and Technology, 7005 Trondheim</wicri:regionArea></affiliation><affiliation wicri:level="1"><mods:affiliation>∗ On sabbatical leave from the Jordan University of Science and Technology, Irbid, Jordan.</mods:affiliation><country xml:lang="fr">Jordanie</country><wicri:regionArea>∗ On sabbatical leave from the Jordan University of Science and Technology, Irbid</wicri:regionArea></affiliation></author><author><name sortKey="Zahlsen, K" sort="Zahlsen, K" uniqKey="Zahlsen K" first="K." last="Zahlsen">K. Zahlsen</name><affiliation wicri:level="1"><mods:affiliation>Department of Medical Genetics, Regional Hospital, Eirik Jarls gate 10, 7006 Trondheim, Norway</mods:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Medical Genetics, Regional Hospital, Eirik Jarls gate 10, 7006 Trondheim</wicri:regionArea></affiliation></author><author><name sortKey="Idle, J R" sort="Idle, J R" uniqKey="Idle J" first="J. R." last="Idle">J. R. Idle</name><affiliation><mods:affiliation>Author for correspondence.</mods:affiliation><wicri:noCountry code="no comma">Author for correspondence.</wicri:noCountry></affiliation><affiliation wicri:level="1"><mods:affiliation>Institute for Cancer Research and Molecular Biology, Norwegian University of Science and Technology, 7005 Trondheim, Norway</mods:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Institute for Cancer Research and Molecular Biology, Norwegian University of Science and Technology, 7005 Trondheim</wicri:regionArea></affiliation><affiliation wicri:level="1"><mods:affiliation>Department of Medical Genetics, Regional Hospital, Eirik Jarls gate 10, 7006 Trondheim, Norway</mods:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Medical Genetics, Regional Hospital, Eirik Jarls gate 10, 7006 Trondheim</wicri:regionArea></affiliation></author><author><name sortKey="Cholerton, S" sort="Cholerton, S" uniqKey="Cholerton S" first="S." last="Cholerton">S. Cholerton</name><affiliation wicri:level="1"><mods:affiliation>Pharmacogenetics Research Unit, Department of Pharmacological Sciences, Medical School, University of Newcastle, Newcastle upon Tyne NE2 4HH, UK</mods:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Pharmacogenetics Research Unit, Department of Pharmacological Sciences, Medical School, University of Newcastle, Newcastle upon Tyne NE2 4HH</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:16EF93B8E34A83E40226DA46C8BB208D6C8AB35B</idno><date when="1997" year="1997">1997</date><idno type="doi">10.1016/S0278-6915(97)00066-5</idno><idno type="url">https://api.istex.fr/document/16EF93B8E34A83E40226DA46C8BB208D6C8AB35B/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">000A68</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">000A68</idno><idno type="wicri:Area/Istex/Curation">000A68</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">A single amino acid substitution (Leu160His) in cytochrome P 450 CYP2A6 causes switching from 7-hydroxylation to 3-hydroxylation of coumarin</title><author><name sortKey="Hadidi, H" sort="Hadidi, H" uniqKey="Hadidi H" first="H." last="Hadidi">H. Hadidi</name><affiliation wicri:level="1"><mods:affiliation>Institute for Cancer Research and Molecular Biology, Norwegian University of Science and Technology, 7005 Trondheim, Norway</mods:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Institute for Cancer Research and Molecular Biology, Norwegian University of Science and Technology, 7005 Trondheim</wicri:regionArea></affiliation><affiliation wicri:level="1"><mods:affiliation>∗ On sabbatical leave from the Jordan University of Science and Technology, Irbid, Jordan.</mods:affiliation><country xml:lang="fr">Jordanie</country><wicri:regionArea>∗ On sabbatical leave from the Jordan University of Science and Technology, Irbid</wicri:regionArea></affiliation></author><author><name sortKey="Zahlsen, K" sort="Zahlsen, K" uniqKey="Zahlsen K" first="K." last="Zahlsen">K. Zahlsen</name><affiliation wicri:level="1"><mods:affiliation>Department of Medical Genetics, Regional Hospital, Eirik Jarls gate 10, 7006 Trondheim, Norway</mods:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Medical Genetics, Regional Hospital, Eirik Jarls gate 10, 7006 Trondheim</wicri:regionArea></affiliation></author><author><name sortKey="Idle, J R" sort="Idle, J R" uniqKey="Idle J" first="J. R." last="Idle">J. R. Idle</name><affiliation><mods:affiliation>Author for correspondence.</mods:affiliation></affiliation><affiliation wicri:level="1"><mods:affiliation>Institute for Cancer Research and Molecular Biology, Norwegian University of Science and Technology, 7005 Trondheim, Norway</mods:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Institute for Cancer Research and Molecular Biology, Norwegian University of Science and Technology, 7005 Trondheim</wicri:regionArea></affiliation><affiliation wicri:level="1"><mods:affiliation>Department of Medical Genetics, Regional Hospital, Eirik Jarls gate 10, 7006 Trondheim, Norway</mods:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Medical Genetics, Regional Hospital, Eirik Jarls gate 10, 7006 Trondheim</wicri:regionArea></affiliation></author><author><name sortKey="Cholerton, S" sort="Cholerton, S" uniqKey="Cholerton S" first="S." last="Cholerton">S. Cholerton</name><affiliation wicri:level="1"><mods:affiliation>Pharmacogenetics Research Unit, Department of Pharmacological Sciences, Medical School, University of Newcastle, Newcastle upon Tyne NE2 4HH, UK</mods:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Pharmacogenetics Research Unit, Department of Pharmacological Sciences, Medical School, University of Newcastle, Newcastle upon Tyne NE2 4HH</wicri:regionArea></affiliation></author></analytic><monogr></monogr><series><title level="j">Food and Chemical Toxicology</title><title level="j" type="abbrev">FCT</title><idno type="ISSN">0278-6915</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1997">1997</date><biblScope unit="volume">35</biblScope><biblScope unit="issue">9</biblScope><biblScope unit="page" from="903">903</biblScope><biblScope unit="page" to="907">907</biblScope></imprint><idno type="ISSN">0278-6915</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0278-6915</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Human populations are thought to metabolize coumarin almost exclusively by 7-hydroxylation. We have identified an individual who is homozygous for a single amino acid substitution (Leul60His) in the cytochrome P450 CYP2A6 arising from the variant CYP2A6∗2 allele. On administration of coumarin (2 mg orally) no detectable 7-hydroxycoumarin was excreted in the 0–8-hr urine, rather, approximately 50% of the dose was eliminated as 2-hydroxyphenylacetic acid, the end-product of coumarin 3-hydroxylation. His immediate family members, who were heterozygous for the CYP2A6∗2 allele, excreted little 2-hydroxyphenylacetic acid and mainly 7-hydroxycoumarin, when similarly tested. These findings raise a question regarding human risk evaluations for environmental coumarin exposures, since 7-hydroxylation is regarded as a detoxication pathway, but 3-hydroxylation as the process required to lead to macromolecular covalent binding of coumarin. Persons homozygous for the CYP2A6∗2 allele may constitute 1–25% of various populations.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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