Functional evaluation of polymorphisms in the human ABCB1 gene and the impact on clinical responses of antiepileptic drugs
OBJECTIVEThe ABCB1 haplotype combinations have been demonstrated to be associated with epilepsy treatment outcomes. The aim of this study is to investigate whether ABCB1 haplotype combinations would affect P-glycoprotein (Pgp) function and impact the clinical responses of antiepileptic drugs (AEDs)....
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| Veröffentlicht in: | Pharmacogenetics and genomics 2008-05, Vol.18 (5), p.390-402 |
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| creator | Hung, Chin-Chuan Chen, Chih-Chuan Lin, Chun-Jung Liou, Horng-Huei |
| description | OBJECTIVEThe ABCB1 haplotype combinations have been demonstrated to be associated with epilepsy treatment outcomes. The aim of this study is to investigate whether ABCB1 haplotype combinations would affect P-glycoprotein (Pgp) function and impact the clinical responses of antiepileptic drugs (AEDs).
METHODS AND RESULTSTransport of substrate rhodamine 123 and calcein-AM by human Pgp carrying 12 haplotype combinations of 1236C>T, 2677G>T/A and 3435C>T were assayed in the absence and presence of known inhibitors and AEDs. The inhibitory potency of the tested drugs from the dose–response relationships was cyclosporin A>verapamil> phenytoin> carbamazepine> lamotrigine>phenobarbital>valproic acid, levetiracetam, gabapentin. The silent polymorphisms combination (1236T-3435T) and triple haplotypes (1236T-2677A/T-3435T) resulted in profoundly less effective inhibition against substrates with significantly lower intracellular substrate concentration. These results confirmed that ABCB1 polymorphisms were associated with clinical responses of AEDs.
CONCLUSIONOur findings demonstrated that human ABCB1 polymorphisms may alter the interactions between Pgp and substrates, and provided functional evidence for ABCB1 haplotypes-associated epilepsy treatment responses. |
| doi_str_mv | 10.1097/FPC.0b013e3282f85e36 |
| format | Article |
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METHODS AND RESULTSTransport of substrate rhodamine 123 and calcein-AM by human Pgp carrying 12 haplotype combinations of 1236C>T, 2677G>T/A and 3435C>T were assayed in the absence and presence of known inhibitors and AEDs. The inhibitory potency of the tested drugs from the dose–response relationships was cyclosporin A>verapamil> phenytoin> carbamazepine> lamotrigine>phenobarbital>valproic acid, levetiracetam, gabapentin. The silent polymorphisms combination (1236T-3435T) and triple haplotypes (1236T-2677A/T-3435T) resulted in profoundly less effective inhibition against substrates with significantly lower intracellular substrate concentration. These results confirmed that ABCB1 polymorphisms were associated with clinical responses of AEDs.
CONCLUSIONOur findings demonstrated that human ABCB1 polymorphisms may alter the interactions between Pgp and substrates, and provided functional evidence for ABCB1 haplotypes-associated epilepsy treatment responses.</description><identifier>ISSN: 1744-6872</identifier><identifier>EISSN: 1744-6880</identifier><identifier>DOI: 10.1097/FPC.0b013e3282f85e36</identifier><identifier>PMID: 18408562</identifier><language>eng</language><publisher>Hagerstown, MD: Lippincott Williams & Wilkins, Inc</publisher><subject>Anticonvulsants - pharmacology ; Anticonvulsants - therapeutic use ; ATP Binding Cassette Transporter, Sub-Family B ; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics ; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism ; ATP-Binding Cassette, Sub-Family B, Member 1 - physiology ; Base Sequence ; Biological and medical sciences ; Cells, Cultured ; Dose-Response Relationship, Drug ; Drug Resistance - genetics ; Epilepsy - diagnosis ; Epilepsy - drug therapy ; Epilepsy - genetics ; Fluoresceins - pharmacokinetics ; Fluorescent Dyes - pharmacokinetics ; General pharmacology ; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy ; Humans ; Medical sciences ; Nervous system (semeiology, syndromes) ; Neurology ; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions ; Pharmacology. Drug treatments ; Polymorphism, Single Nucleotide - physiology ; Prognosis ; Rhodamine 123 - pharmacokinetics</subject><ispartof>Pharmacogenetics and genomics, 2008-05, Vol.18 (5), p.390-402</ispartof><rights>2008 Lippincott Williams & Wilkins, Inc.</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4463-cf651d2601c426ace6a1a717e2268a6e1c8dc1acad8138f8422372a3f34a7c2e3</citedby><cites>FETCH-LOGICAL-c4463-cf651d2601c426ace6a1a717e2268a6e1c8dc1acad8138f8422372a3f34a7c2e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20272708$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18408562$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hung, Chin-Chuan</creatorcontrib><creatorcontrib>Chen, Chih-Chuan</creatorcontrib><creatorcontrib>Lin, Chun-Jung</creatorcontrib><creatorcontrib>Liou, Horng-Huei</creatorcontrib><title>Functional evaluation of polymorphisms in the human ABCB1 gene and the impact on clinical responses of antiepileptic drugs</title><title>Pharmacogenetics and genomics</title><addtitle>Pharmacogenet Genomics</addtitle><description>OBJECTIVEThe ABCB1 haplotype combinations have been demonstrated to be associated with epilepsy treatment outcomes. The aim of this study is to investigate whether ABCB1 haplotype combinations would affect P-glycoprotein (Pgp) function and impact the clinical responses of antiepileptic drugs (AEDs).
METHODS AND RESULTSTransport of substrate rhodamine 123 and calcein-AM by human Pgp carrying 12 haplotype combinations of 1236C>T, 2677G>T/A and 3435C>T were assayed in the absence and presence of known inhibitors and AEDs. The inhibitory potency of the tested drugs from the dose–response relationships was cyclosporin A>verapamil> phenytoin> carbamazepine> lamotrigine>phenobarbital>valproic acid, levetiracetam, gabapentin. The silent polymorphisms combination (1236T-3435T) and triple haplotypes (1236T-2677A/T-3435T) resulted in profoundly less effective inhibition against substrates with significantly lower intracellular substrate concentration. These results confirmed that ABCB1 polymorphisms were associated with clinical responses of AEDs.
CONCLUSIONOur findings demonstrated that human ABCB1 polymorphisms may alter the interactions between Pgp and substrates, and provided functional evidence for ABCB1 haplotypes-associated epilepsy treatment responses.</description><subject>Anticonvulsants - pharmacology</subject><subject>Anticonvulsants - therapeutic use</subject><subject>ATP Binding Cassette Transporter, Sub-Family B</subject><subject>ATP-Binding Cassette, Sub-Family B, Member 1 - genetics</subject><subject>ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism</subject><subject>ATP-Binding Cassette, Sub-Family B, Member 1 - physiology</subject><subject>Base Sequence</subject><subject>Biological and medical sciences</subject><subject>Cells, Cultured</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Resistance - genetics</subject><subject>Epilepsy - diagnosis</subject><subject>Epilepsy - drug therapy</subject><subject>Epilepsy - genetics</subject><subject>Fluoresceins - pharmacokinetics</subject><subject>Fluorescent Dyes - pharmacokinetics</subject><subject>General pharmacology</subject><subject>Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Nervous system (semeiology, syndromes)</subject><subject>Neurology</subject><subject>Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions</subject><subject>Pharmacology. Drug treatments</subject><subject>Polymorphism, Single Nucleotide - physiology</subject><subject>Prognosis</subject><subject>Rhodamine 123 - pharmacokinetics</subject><issn>1744-6872</issn><issn>1744-6880</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkMFu1DAQhiMEoqXwBgj5AreUGdtru8d2xdJKleAA52jqTBqD4wQ7oSpPT5auWomDZVv-_n-sr6reIpwinNmPu6_bU7gBVKykk53bsDLPqmO0WtfGOXj-eLbyqHpVyg8AZc60fFkdodPgNkYeV392S_JzGBNFwb8pLrS_iLET0xjvhzFPfShDESGJuWfRLwMlcX6xvUBxy4kFpfbfQxgm8rNYoz6GFPxal7lMYypc9m2U5sBTiDzNwYs2L7fldfWio1j4zWE_qb7vPn3bXtbXXz5fbc-va6-1UbXvzAZbaQC9loY8G0KyaFlK48gwetd6JE-tQ-U6p6VUVpLqlCbrJauT6sND75THXwuXuRlC8RwjJR6X0ljYgHUIK6gfQJ_HUjJ3zZTDQPm-QWj2zpvVefO_8zX27tC_3AzcPoUOklfg_QGgsorpMiUfyiMnQVppwT3NvxvjzLn8jMsd56ZninPfAEpUgFhLALd-GaBeFyj1F6Jym9k</recordid><startdate>200805</startdate><enddate>200805</enddate><creator>Hung, Chin-Chuan</creator><creator>Chen, Chih-Chuan</creator><creator>Lin, Chun-Jung</creator><creator>Liou, Horng-Huei</creator><general>Lippincott Williams & Wilkins, Inc</general><general>Lippincott Williams and Wilkins</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>7X8</scope></search><sort><creationdate>200805</creationdate><title>Functional evaluation of polymorphisms in the human ABCB1 gene and the impact on clinical responses of antiepileptic drugs</title><author>Hung, Chin-Chuan ; Chen, Chih-Chuan ; Lin, Chun-Jung ; Liou, Horng-Huei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4463-cf651d2601c426ace6a1a717e2268a6e1c8dc1acad8138f8422372a3f34a7c2e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Anticonvulsants - pharmacology</topic><topic>Anticonvulsants - therapeutic use</topic><topic>ATP Binding Cassette Transporter, Sub-Family B</topic><topic>ATP-Binding Cassette, Sub-Family B, Member 1 - genetics</topic><topic>ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism</topic><topic>ATP-Binding Cassette, Sub-Family B, Member 1 - physiology</topic><topic>Base Sequence</topic><topic>Biological and medical sciences</topic><topic>Cells, Cultured</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Resistance - genetics</topic><topic>Epilepsy - diagnosis</topic><topic>Epilepsy - drug therapy</topic><topic>Epilepsy - genetics</topic><topic>Fluoresceins - pharmacokinetics</topic><topic>Fluorescent Dyes - pharmacokinetics</topic><topic>General pharmacology</topic><topic>Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Nervous system (semeiology, syndromes)</topic><topic>Neurology</topic><topic>Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions</topic><topic>Pharmacology. Drug treatments</topic><topic>Polymorphism, Single Nucleotide - physiology</topic><topic>Prognosis</topic><topic>Rhodamine 123 - pharmacokinetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hung, Chin-Chuan</creatorcontrib><creatorcontrib>Chen, Chih-Chuan</creatorcontrib><creatorcontrib>Lin, Chun-Jung</creatorcontrib><creatorcontrib>Liou, Horng-Huei</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>MEDLINE - Academic</collection><jtitle>Pharmacogenetics and genomics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hung, Chin-Chuan</au><au>Chen, Chih-Chuan</au><au>Lin, Chun-Jung</au><au>Liou, Horng-Huei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Functional evaluation of polymorphisms in the human ABCB1 gene and the impact on clinical responses of antiepileptic drugs</atitle><jtitle>Pharmacogenetics and genomics</jtitle><addtitle>Pharmacogenet Genomics</addtitle><date>2008-05</date><risdate>2008</risdate><volume>18</volume><issue>5</issue><spage>390</spage><epage>402</epage><pages>390-402</pages><issn>1744-6872</issn><eissn>1744-6880</eissn><abstract>OBJECTIVEThe ABCB1 haplotype combinations have been demonstrated to be associated with epilepsy treatment outcomes. The aim of this study is to investigate whether ABCB1 haplotype combinations would affect P-glycoprotein (Pgp) function and impact the clinical responses of antiepileptic drugs (AEDs).
METHODS AND RESULTSTransport of substrate rhodamine 123 and calcein-AM by human Pgp carrying 12 haplotype combinations of 1236C>T, 2677G>T/A and 3435C>T were assayed in the absence and presence of known inhibitors and AEDs. The inhibitory potency of the tested drugs from the dose–response relationships was cyclosporin A>verapamil> phenytoin> carbamazepine> lamotrigine>phenobarbital>valproic acid, levetiracetam, gabapentin. The silent polymorphisms combination (1236T-3435T) and triple haplotypes (1236T-2677A/T-3435T) resulted in profoundly less effective inhibition against substrates with significantly lower intracellular substrate concentration. These results confirmed that ABCB1 polymorphisms were associated with clinical responses of AEDs.
CONCLUSIONOur findings demonstrated that human ABCB1 polymorphisms may alter the interactions between Pgp and substrates, and provided functional evidence for ABCB1 haplotypes-associated epilepsy treatment responses.</abstract><cop>Hagerstown, MD</cop><pub>Lippincott Williams & Wilkins, Inc</pub><pmid>18408562</pmid><doi>10.1097/FPC.0b013e3282f85e36</doi><tpages>13</tpages></addata></record> |
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| subjects | Anticonvulsants - pharmacology Anticonvulsants - therapeutic use ATP Binding Cassette Transporter, Sub-Family B ATP-Binding Cassette, Sub-Family B, Member 1 - genetics ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism ATP-Binding Cassette, Sub-Family B, Member 1 - physiology Base Sequence Biological and medical sciences Cells, Cultured Dose-Response Relationship, Drug Drug Resistance - genetics Epilepsy - diagnosis Epilepsy - drug therapy Epilepsy - genetics Fluoresceins - pharmacokinetics Fluorescent Dyes - pharmacokinetics General pharmacology Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy Humans Medical sciences Nervous system (semeiology, syndromes) Neurology Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions Pharmacology. Drug treatments Polymorphism, Single Nucleotide - physiology Prognosis Rhodamine 123 - pharmacokinetics |
| title | Functional evaluation of polymorphisms in the human ABCB1 gene and the impact on clinical responses of antiepileptic drugs |
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