Abstract:
OBJECTIVE:Nicotine, the main addictive ingredient in tobacco, is metabolically inactivated to cotinine primarily by the hepatic enzyme CYP2A6. Considerable genetic variation in the CYP2A6 gene results in large variation in the rates of nicotine metabolism, which in turn alters smoking behaviours (e.g. amount of cigarettes smoked, risk for dependence and success in smoking cessation). The aim of this study was to identify and characterize novel variants in CYP2A6. MATERIALS AND METHODS:The CYP2A6 gene from African American phenotypically slow nicotine metabolizers was sequenced and seven novel variants were identified [CYP2A6*39 (V68M), CYP2A6*40 (I149M), CYP2A6*41 (R265Q), CYP2A6*42 (I268T), CYP2A6*43 (T303I), CYP2A6*44 (E390K), CYP2A6*44 (L462P)]. Variants were introduced into a bi-cistronic cDNA expression construct containing CYP2A6 and P450 oxidoreductase and assessed for protein expression, enzymatic activity and stability as evaluated using western blotting and nicotine metabolism. Genotyping assays were developed and allelic frequencies were assessed in 534 African Americans. RESULTS:The variants showed significantly lower protein expression (P<0.001) when compared with the wild-type as well as reduced metabolism of nicotine to cotinine when controlling for cDNA expression using P450 oxidoreductase (P<0.001). The variants also showed reduced stability at 37°C. Allelic frequencies ranged from 0.1 to 0.6% with a collective genotype frequency of 3.2%; the impact in vitro correlated significantly with in-vivo activity (R(2)=0.40-0.48, P<0.05). Together, those with a novel variant had significantly lower nicotine metabolism in vivo than those without genetic variants (P<0.01). CONCLUSION:Here, we identified a number of novel variants with reduced/loss of CYP2A6 activity, increasing our understanding of CYP2A6 genetic variability.
journal_name
Pharmacogenet Genomicsjournal_title
Pharmacogenetics and genomicsauthors
Piliguian M,Zhu AZ,Zhou Q,Benowitz NL,Ahluwalia JS,Sanderson Cox L,Tyndale RFdoi
10.1097/FPC.0000000000000026subject
Has Abstractpub_date
2014-02-01 00:00:00pages
118-28issue
2eissn
1744-6872issn
1744-6880journal_volume
24pub_type
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journal_title:Pharmacogenetics and genomics
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journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
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journal_title:Pharmacogenetics and genomics
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doi:10.1097/FPC.0b013e32801112b5
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journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章,meta分析,评审
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更新日期:2013-10-01 00:00:00
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journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1097/FPC.0b013e3282fa760a
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pub_type: 临床试验,杂志文章,多中心研究
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更新日期:2009-06-01 00:00:00
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pub_type: 杂志文章,meta分析,评审
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更新日期:2014-07-01 00:00:00
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doi:10.1097/FPC.0b013e32834911d0
更新日期:2011-09-01 00:00:00
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journal_title:Pharmacogenetics and genomics
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doi:10.1097/FPC.0b013e328328d4e9
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pub_type: 临床试验,杂志文章,多中心研究
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更新日期:2010-05-01 00:00:00
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更新日期:2011-09-01 00:00:00
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更新日期:2014-05-01 00:00:00
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pub_type: 杂志文章
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更新日期:2006-02-01 00:00:00
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journal_title:Pharmacogenetics and genomics
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更新日期:2007-02-01 00:00:00
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更新日期:2014-08-01 00:00:00