The neuroprotective enzyme CYP2D6 increases in the brain with age and is lower in Parkinson's disease patients.
Identifieur interne : 001104 ( Main/Exploration ); précédent : 001103; suivant : 001105The neuroprotective enzyme CYP2D6 increases in the brain with age and is lower in Parkinson's disease patients.
Auteurs : Amandeep Mann [Canada] ; Sharon L. Miksys ; Andrea Gaedigk ; Stephen J. Kish ; Deborah C. Mash ; Rachel F. TyndaleSource :
- Neurobiology of aging [ 1558-1497 ] ; 2012.
English descriptors
- KwdEn :
- Adolescent, Adult, Age Factors, Aged, Brain (embryology), Brain (enzymology), Brain (growth & development), Case-Control Studies, Child, Child, Preschool, Cytochrome P-450 CYP2D6 (metabolism), Female, Fetus, Gene Expression Regulation, Developmental (physiology), Genotype, Humans, Infant, Infant, Newborn, Male, Middle Aged, Parkinson Disease (enzymology), Parkinson Disease (genetics), Parkinson Disease (pathology), Postmortem Changes, Young Adult.
- MESH :
- chemical , metabolism : Cytochrome P-450 CYP2D6.
- embryology : Brain.
- enzymology : Brain, Parkinson Disease.
- genetics : Parkinson Disease.
- growth & development : Brain.
- pathology : Parkinson Disease.
- physiology : Gene Expression Regulation, Developmental.
- Adolescent, Adult, Age Factors, Aged, Case-Control Studies, Child, Child, Preschool, Female, Fetus, Genotype, Humans, Infant, Infant, Newborn, Male, Middle Aged, Postmortem Changes, Young Adult.
Abstract
Cytochrome P450 2D6 (CYP2D6) is a drug-metabolizing enzyme expressed in the brain that also metabolizes endogenous neural compounds (e.g., catecholamines) and inactivates neurotoxins (e.g., 1-methyl-4-thenyl-1,2,3,6-tetrahydropyridine; MPTP). Genetically poor CYP2D6 metabolizers are at higher risk for developing Parkinson's disease (PD), a risk that increases with exposure to pesticides. As age is a risk factor for PD we measured the ontogenic expression of CYP2D6 in human brain, and compared brain CYP2D6 levels in PD cases with age-matched controls. CYP2D6 increased from fetal to 80 years of age (n = 76), exhibiting 3 distinct phases of change. Compared with PD controls, PD cases had approximately 40% lower CYP2D6 levels in the frontal cortex, cerebellum, and the hippocampus, even when controlling for CYP2D6 genotype. In contrast, CYP2D6 levels in cases were similar to controls in PD-affected brain areas, the substantia nigra, and caudate, consistent with higher astrocytic and cellular CYP2D6 staining observed in PD cases. In summary, the lower CYP2D6 levels in PD cases may have reduced their ability to inactivate PD-causing neurotoxins contributing to their disease risk.
DOI: 10.1016/j.neurobiolaging.2011.08.014
PubMed: 21958961
Affiliations:
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Miksys</name></author><author><name sortKey="Gaedigk, Andrea" sort="Gaedigk, Andrea" uniqKey="Gaedigk A" first="Andrea" last="Gaedigk">Andrea Gaedigk</name></author><author><name sortKey="Kish, Stephen J" sort="Kish, Stephen J" uniqKey="Kish S" first="Stephen J" last="Kish">Stephen J. Kish</name></author><author><name sortKey="Mash, Deborah C" sort="Mash, Deborah C" uniqKey="Mash D" first="Deborah C" last="Mash">Deborah C. Mash</name></author><author><name sortKey="Tyndale, Rachel F" sort="Tyndale, Rachel F" uniqKey="Tyndale R" first="Rachel F" last="Tyndale">Rachel F. Tyndale</name></author></analytic><series><title level="j">Neurobiology of aging</title><idno type="eISSN">1558-1497</idno><imprint><date when="2012" type="published">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adolescent</term><term>Adult</term><term>Age Factors</term><term>Aged</term><term>Brain (embryology)</term><term>Brain (enzymology)</term><term>Brain (growth & development)</term><term>Case-Control Studies</term><term>Child</term><term>Child, Preschool</term><term>Cytochrome P-450 CYP2D6 (metabolism)</term><term>Female</term><term>Fetus</term><term>Gene Expression Regulation, Developmental (physiology)</term><term>Genotype</term><term>Humans</term><term>Infant</term><term>Infant, Newborn</term><term>Male</term><term>Middle Aged</term><term>Parkinson Disease (enzymology)</term><term>Parkinson Disease (genetics)</term><term>Parkinson Disease (pathology)</term><term>Postmortem Changes</term><term>Young Adult</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Cytochrome P-450 CYP2D6</term></keywords><keywords scheme="MESH" qualifier="embryology" xml:lang="en"><term>Brain</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Brain</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="growth & development" xml:lang="en"><term>Brain</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Gene Expression Regulation, Developmental</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adolescent</term><term>Adult</term><term>Age Factors</term><term>Aged</term><term>Case-Control Studies</term><term>Child</term><term>Child, Preschool</term><term>Female</term><term>Fetus</term><term>Genotype</term><term>Humans</term><term>Infant</term><term>Infant, Newborn</term><term>Male</term><term>Middle Aged</term><term>Postmortem Changes</term><term>Young Adult</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Cytochrome P450 2D6 (CYP2D6) is a drug-metabolizing enzyme expressed in the brain that also metabolizes endogenous neural compounds (e.g., catecholamines) and inactivates neurotoxins (e.g., 1-methyl-4-thenyl-1,2,3,6-tetrahydropyridine; MPTP). Genetically poor CYP2D6 metabolizers are at higher risk for developing Parkinson's disease (PD), a risk that increases with exposure to pesticides. As age is a risk factor for PD we measured the ontogenic expression of CYP2D6 in human brain, and compared brain CYP2D6 levels in PD cases with age-matched controls. CYP2D6 increased from fetal to 80 years of age (n = 76), exhibiting 3 distinct phases of change. Compared with PD controls, PD cases had approximately 40% lower CYP2D6 levels in the frontal cortex, cerebellum, and the hippocampus, even when controlling for CYP2D6 genotype. In contrast, CYP2D6 levels in cases were similar to controls in PD-affected brain areas, the substantia nigra, and caudate, consistent with higher astrocytic and cellular CYP2D6 staining observed in PD cases. In summary, the lower CYP2D6 levels in PD cases may have reduced their ability to inactivate PD-causing neurotoxins contributing to their disease risk.</div></front></TEI><affiliations><list><country><li>Canada</li></country><region><li>Ontario</li></region><settlement><li>Toronto</li></settlement><orgName><li>Université de Toronto</li></orgName></list><tree><noCountry><name sortKey="Gaedigk, Andrea" sort="Gaedigk, Andrea" uniqKey="Gaedigk A" first="Andrea" last="Gaedigk">Andrea Gaedigk</name><name sortKey="Kish, Stephen J" sort="Kish, Stephen J" uniqKey="Kish S" first="Stephen J" last="Kish">Stephen J. Kish</name><name sortKey="Mash, Deborah C" sort="Mash, Deborah C" uniqKey="Mash D" first="Deborah C" last="Mash">Deborah C. Mash</name><name sortKey="Miksys, Sharon L" sort="Miksys, Sharon L" uniqKey="Miksys S" first="Sharon L" last="Miksys">Sharon L. Miksys</name><name sortKey="Tyndale, Rachel F" sort="Tyndale, Rachel F" uniqKey="Tyndale R" first="Rachel F" last="Tyndale">Rachel F. Tyndale</name></noCountry><country name="Canada"><region name="Ontario"><name sortKey="Mann, Amandeep" sort="Mann, Amandeep" uniqKey="Mann A" first="Amandeep" last="Mann">Amandeep Mann</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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