Regional and cellular expression of CYP2D6 in human brain: higher levels in alcoholics
Cytochrome P450 (CYP) 2D6 is expressed in liver, brain and other extrahepatic tissues where it metabolizes a range of centrally acting drugs and toxins. As ethanol can induce CYP2D in rat brain, we hypothesized that CYP2D6 expression is higher in brains of human alcoholics. We examined regional and...
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| Veröffentlicht in: | Journal of neurochemistry 2002-09, Vol.82 (6), p.1376-1387 |
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| creator | Miksys, Sharon Rao, Yushu Hoffmann, Ewa Mash, Deborah C. Tyndale, Rachel F. |
| description | Cytochrome P450 (CYP) 2D6 is expressed in liver, brain and other extrahepatic tissues where it metabolizes a range of centrally acting drugs and toxins. As ethanol can induce CYP2D in rat brain, we hypothesized that CYP2D6 expression is higher in brains of human alcoholics. We examined regional and cellular expression of CYP2D6 mRNA and protein by RT‐PCR, Southern blotting, slot blotting, immunoblotting and immunocytochemistry. A significant correlation was found between mean mRNA and CYP2D6 protein levels across 13 brain regions. Higher expression was detected in 13 brain regions of alcoholics (n = 8) compared to nonalcoholics (n = 5) (anovap |
| doi_str_mv | 10.1046/j.1471-4159.2002.01069.x |
| format | Article |
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As ethanol can induce CYP2D in rat brain, we hypothesized that CYP2D6 expression is higher in brains of human alcoholics. We examined regional and cellular expression of CYP2D6 mRNA and protein by RT‐PCR, Southern blotting, slot blotting, immunoblotting and immunocytochemistry. A significant correlation was found between mean mRNA and CYP2D6 protein levels across 13 brain regions. Higher expression was detected in 13 brain regions of alcoholics (n = 8) compared to nonalcoholics (n = 5) (anovap < 0.0001). In hippocampus this was localized in CA1–3 pyramidal cells and dentate gyrus granular neurons. In cerebellum this was localized in Purkinje cells and their dendrites. Both of these brain regions, and these same cell‐types, are known to be susceptible to alcohol damage. For one case, a poor metabolizer (CYP2D6*4/*4), there was no detectable CYP2D6 protein, confirming the specificity of the antibody used. These data suggest that in alcoholics elevated brain CYP2D6 expression may contribute to altered sensitivity to centrally acting drugs and to the mediation of neurotoxic and behavioral effects of alcohol.</description><identifier>ISSN: 0022-3042</identifier><identifier>EISSN: 1471-4159</identifier><identifier>DOI: 10.1046/j.1471-4159.2002.01069.x</identifier><identifier>PMID: 12354285</identifier><identifier>CODEN: JONRA9</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Science Ltd</publisher><subject>Adult ; Aged ; alcoholism ; Alcoholism - enzymology ; Alcoholism - pathology ; Alcoholism and acute alcohol poisoning ; Antibody Specificity ; Biological and medical sciences ; Blotting, Southern ; Brain - enzymology ; Brain - pathology ; Brain Chemistry ; Cerebellum - enzymology ; Cerebellum - pathology ; Cytochrome P-450 CYP2D6 - analysis ; Cytochrome P-450 CYP2D6 - biosynthesis ; Cytochrome P-450 CYP2D6 - genetics ; cytochrome P450 CYP2D6 ; drug metabolism ; Frontal Lobe - enzymology ; Frontal Lobe - pathology ; Genotype ; Hippocampus - enzymology ; Hippocampus - pathology ; human brain ; Humans ; Immunoblotting ; Immunohistochemistry ; Medical sciences ; Middle Aged ; Neurons - enzymology ; Neurons - pathology ; neurotoxicity ; Organ Specificity ; Purkinje Cells - enzymology ; Purkinje Cells - pathology ; Pyramidal Cells - enzymology ; Pyramidal Cells - pathology ; RNA, Messenger - analysis ; RNA, Messenger - biosynthesis ; Smoking - metabolism ; Smoking - pathology ; Toxicology</subject><ispartof>Journal of neurochemistry, 2002-09, Vol.82 (6), p.1376-1387</ispartof><rights>2003 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4929-a7c7ee9b55c6ef36a2d15d8f0841431524de347550ccb1fde857f7c19e0f582e3</citedby><cites>FETCH-LOGICAL-c4929-a7c7ee9b55c6ef36a2d15d8f0841431524de347550ccb1fde857f7c19e0f582e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1046%2Fj.1471-4159.2002.01069.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1046%2Fj.1471-4159.2002.01069.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,1433,27924,27925,45574,45575,46409,46833</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=13927901$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12354285$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Miksys, Sharon</creatorcontrib><creatorcontrib>Rao, Yushu</creatorcontrib><creatorcontrib>Hoffmann, Ewa</creatorcontrib><creatorcontrib>Mash, Deborah C.</creatorcontrib><creatorcontrib>Tyndale, Rachel F.</creatorcontrib><title>Regional and cellular expression of CYP2D6 in human brain: higher levels in alcoholics</title><title>Journal of neurochemistry</title><addtitle>J Neurochem</addtitle><description>Cytochrome P450 (CYP) 2D6 is expressed in liver, brain and other extrahepatic tissues where it metabolizes a range of centrally acting drugs and toxins. As ethanol can induce CYP2D in rat brain, we hypothesized that CYP2D6 expression is higher in brains of human alcoholics. We examined regional and cellular expression of CYP2D6 mRNA and protein by RT‐PCR, Southern blotting, slot blotting, immunoblotting and immunocytochemistry. A significant correlation was found between mean mRNA and CYP2D6 protein levels across 13 brain regions. Higher expression was detected in 13 brain regions of alcoholics (n = 8) compared to nonalcoholics (n = 5) (anovap < 0.0001). In hippocampus this was localized in CA1–3 pyramidal cells and dentate gyrus granular neurons. In cerebellum this was localized in Purkinje cells and their dendrites. Both of these brain regions, and these same cell‐types, are known to be susceptible to alcohol damage. For one case, a poor metabolizer (CYP2D6*4/*4), there was no detectable CYP2D6 protein, confirming the specificity of the antibody used. These data suggest that in alcoholics elevated brain CYP2D6 expression may contribute to altered sensitivity to centrally acting drugs and to the mediation of neurotoxic and behavioral effects of alcohol.</description><subject>Adult</subject><subject>Aged</subject><subject>alcoholism</subject><subject>Alcoholism - enzymology</subject><subject>Alcoholism - pathology</subject><subject>Alcoholism and acute alcohol poisoning</subject><subject>Antibody Specificity</subject><subject>Biological and medical sciences</subject><subject>Blotting, Southern</subject><subject>Brain - enzymology</subject><subject>Brain - pathology</subject><subject>Brain Chemistry</subject><subject>Cerebellum - enzymology</subject><subject>Cerebellum - pathology</subject><subject>Cytochrome P-450 CYP2D6 - analysis</subject><subject>Cytochrome P-450 CYP2D6 - biosynthesis</subject><subject>Cytochrome P-450 CYP2D6 - genetics</subject><subject>cytochrome P450 CYP2D6</subject><subject>drug metabolism</subject><subject>Frontal Lobe - enzymology</subject><subject>Frontal Lobe - pathology</subject><subject>Genotype</subject><subject>Hippocampus - enzymology</subject><subject>Hippocampus - pathology</subject><subject>human brain</subject><subject>Humans</subject><subject>Immunoblotting</subject><subject>Immunohistochemistry</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Neurons - enzymology</subject><subject>Neurons - pathology</subject><subject>neurotoxicity</subject><subject>Organ Specificity</subject><subject>Purkinje Cells - enzymology</subject><subject>Purkinje Cells - pathology</subject><subject>Pyramidal Cells - enzymology</subject><subject>Pyramidal Cells - pathology</subject><subject>RNA, Messenger - analysis</subject><subject>RNA, Messenger - biosynthesis</subject><subject>Smoking - metabolism</subject><subject>Smoking - pathology</subject><subject>Toxicology</subject><issn>0022-3042</issn><issn>1471-4159</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkM1u1DAURq2Kqp3-vALyBnYJvo4dx0gs0EALVQVVBZVYWR7nuuORJ5nahE7fvgkzoltW19J3Pl_7EEKBlcBE_W5VglBQCJC65IzxkgGrdbk9ILN_wSsyGxNeVEzwY3KS84oxqEUNR-QYeCUFb-SM3N3ifeg7G6ntWuowxiHaRHG7SZjzmNDe0_mvG_6ppqGjy2FtO7pINnTv6TLcLzHRiH8w5im10fXLPgaXz8ihtzHj-X6ekp8Xn3_MvxTX3y-_zj9eF05orgurnELUCyldjb6qLW9Bto1njQBRgeSixUooKZlzC_AtNlJ55UAj87LhWJ2St7t7N6l_GDD_NuuQp1_YDvshG2gUaKXECDY70KU-54TebFJY2_RkgJnJqVmZSZ2Z1JnJqfnr1GzH6uv9jmGxxvaluJc4Am_2gM3ORp9s50J-4SrNlWYwch923GOI-PTfDzBX3-bTqXoG9sqRVQ</recordid><startdate>200209</startdate><enddate>200209</enddate><creator>Miksys, Sharon</creator><creator>Rao, Yushu</creator><creator>Hoffmann, Ewa</creator><creator>Mash, Deborah C.</creator><creator>Tyndale, Rachel F.</creator><general>Blackwell Science Ltd</general><general>Blackwell</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope></search><sort><creationdate>200209</creationdate><title>Regional and cellular expression of CYP2D6 in human brain: higher levels in alcoholics</title><author>Miksys, Sharon ; Rao, Yushu ; Hoffmann, Ewa ; Mash, Deborah C. ; Tyndale, Rachel F.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4929-a7c7ee9b55c6ef36a2d15d8f0841431524de347550ccb1fde857f7c19e0f582e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Adult</topic><topic>Aged</topic><topic>alcoholism</topic><topic>Alcoholism - enzymology</topic><topic>Alcoholism - pathology</topic><topic>Alcoholism and acute alcohol poisoning</topic><topic>Antibody Specificity</topic><topic>Biological and medical sciences</topic><topic>Blotting, Southern</topic><topic>Brain - enzymology</topic><topic>Brain - pathology</topic><topic>Brain Chemistry</topic><topic>Cerebellum - enzymology</topic><topic>Cerebellum - pathology</topic><topic>Cytochrome P-450 CYP2D6 - analysis</topic><topic>Cytochrome P-450 CYP2D6 - biosynthesis</topic><topic>Cytochrome P-450 CYP2D6 - genetics</topic><topic>cytochrome P450 CYP2D6</topic><topic>drug metabolism</topic><topic>Frontal Lobe - enzymology</topic><topic>Frontal Lobe - pathology</topic><topic>Genotype</topic><topic>Hippocampus - enzymology</topic><topic>Hippocampus - pathology</topic><topic>human brain</topic><topic>Humans</topic><topic>Immunoblotting</topic><topic>Immunohistochemistry</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Neurons - enzymology</topic><topic>Neurons - pathology</topic><topic>neurotoxicity</topic><topic>Organ Specificity</topic><topic>Purkinje Cells - enzymology</topic><topic>Purkinje Cells - pathology</topic><topic>Pyramidal Cells - enzymology</topic><topic>Pyramidal Cells - pathology</topic><topic>RNA, Messenger - analysis</topic><topic>RNA, Messenger - biosynthesis</topic><topic>Smoking - metabolism</topic><topic>Smoking - pathology</topic><topic>Toxicology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Miksys, Sharon</creatorcontrib><creatorcontrib>Rao, Yushu</creatorcontrib><creatorcontrib>Hoffmann, Ewa</creatorcontrib><creatorcontrib>Mash, Deborah C.</creatorcontrib><creatorcontrib>Tyndale, Rachel F.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><jtitle>Journal of neurochemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Miksys, Sharon</au><au>Rao, Yushu</au><au>Hoffmann, Ewa</au><au>Mash, Deborah C.</au><au>Tyndale, Rachel F.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Regional and cellular expression of CYP2D6 in human brain: higher levels in alcoholics</atitle><jtitle>Journal of neurochemistry</jtitle><addtitle>J Neurochem</addtitle><date>2002-09</date><risdate>2002</risdate><volume>82</volume><issue>6</issue><spage>1376</spage><epage>1387</epage><pages>1376-1387</pages><issn>0022-3042</issn><eissn>1471-4159</eissn><coden>JONRA9</coden><abstract>Cytochrome P450 (CYP) 2D6 is expressed in liver, brain and other extrahepatic tissues where it metabolizes a range of centrally acting drugs and toxins. As ethanol can induce CYP2D in rat brain, we hypothesized that CYP2D6 expression is higher in brains of human alcoholics. We examined regional and cellular expression of CYP2D6 mRNA and protein by RT‐PCR, Southern blotting, slot blotting, immunoblotting and immunocytochemistry. A significant correlation was found between mean mRNA and CYP2D6 protein levels across 13 brain regions. Higher expression was detected in 13 brain regions of alcoholics (n = 8) compared to nonalcoholics (n = 5) (anovap < 0.0001). In hippocampus this was localized in CA1–3 pyramidal cells and dentate gyrus granular neurons. In cerebellum this was localized in Purkinje cells and their dendrites. Both of these brain regions, and these same cell‐types, are known to be susceptible to alcohol damage. For one case, a poor metabolizer (CYP2D6*4/*4), there was no detectable CYP2D6 protein, confirming the specificity of the antibody used. These data suggest that in alcoholics elevated brain CYP2D6 expression may contribute to altered sensitivity to centrally acting drugs and to the mediation of neurotoxic and behavioral effects of alcohol.</abstract><cop>Oxford, UK</cop><pub>Blackwell Science Ltd</pub><pmid>12354285</pmid><doi>10.1046/j.1471-4159.2002.01069.x</doi><tpages>12</tpages></addata></record> |
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| subjects | Adult Aged alcoholism Alcoholism - enzymology Alcoholism - pathology Alcoholism and acute alcohol poisoning Antibody Specificity Biological and medical sciences Blotting, Southern Brain - enzymology Brain - pathology Brain Chemistry Cerebellum - enzymology Cerebellum - pathology Cytochrome P-450 CYP2D6 - analysis Cytochrome P-450 CYP2D6 - biosynthesis Cytochrome P-450 CYP2D6 - genetics cytochrome P450 CYP2D6 drug metabolism Frontal Lobe - enzymology Frontal Lobe - pathology Genotype Hippocampus - enzymology Hippocampus - pathology human brain Humans Immunoblotting Immunohistochemistry Medical sciences Middle Aged Neurons - enzymology Neurons - pathology neurotoxicity Organ Specificity Purkinje Cells - enzymology Purkinje Cells - pathology Pyramidal Cells - enzymology Pyramidal Cells - pathology RNA, Messenger - analysis RNA, Messenger - biosynthesis Smoking - metabolism Smoking - pathology Toxicology |
| title | Regional and cellular expression of CYP2D6 in human brain: higher levels in alcoholics |
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