CYP2B6 non-coding variation associated with smoking cessation is also associated with differences in allelic expression, splicing, and nicotine metabolism independent of common amino-acid changes.

The Cytochrome P450 2B6 (CYP2B6) enzyme makes a small contribution to hepatic nicotine metabolism relative to CYP2A6, but CYP2B6 is the primary enzyme responsible for metabolism of the smoking cessation drug bupropion. Using CYP2A6 genotype as a covariate, we find that a non-coding polymorphism in C...

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Main Authors: A Joseph Bloom, Maribel Martinez, Li-Shiun Chen, Laura J Bierut, Sharon E Murphy, Alison Goate
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2013-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC3829832?pdf=render
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spelling doaj-2d32d233ebcf4bacaf899890c0976e082020-11-25T00:08:49ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-01811e7970010.1371/journal.pone.0079700CYP2B6 non-coding variation associated with smoking cessation is also associated with differences in allelic expression, splicing, and nicotine metabolism independent of common amino-acid changes.A Joseph BloomMaribel MartinezLi-Shiun ChenLaura J BierutSharon E MurphyAlison GoateThe Cytochrome P450 2B6 (CYP2B6) enzyme makes a small contribution to hepatic nicotine metabolism relative to CYP2A6, but CYP2B6 is the primary enzyme responsible for metabolism of the smoking cessation drug bupropion. Using CYP2A6 genotype as a covariate, we find that a non-coding polymorphism in CYP2B6 previously associated with smoking cessation (rs8109525) is also significantly associated with nicotine metabolism. The association is independent of the well-studied non-synonymous variants rs3211371, rs3745274, and rs2279343 (CYP2B6*5 and *6). Expression studies demonstrate that rs8109525 is also associated with differences in CYP2B6 mRNA expression in liver biopsy samples. Splicing assays demonstrate that specific splice forms of CYP2B6 are associated with haplotypes defined by variants including rs3745274 and rs8109525. These results indicate differences in mRNA expression and splicing as potential molecular mechanisms by which non-coding variation in CYP2B6 may affect enzymatic activity leading to differences in metabolism and smoking cessation.http://europepmc.org/articles/PMC3829832?pdf=render
collection DOAJ
language English
format Article
sources DOAJ
author A Joseph Bloom
Maribel Martinez
Li-Shiun Chen
Laura J Bierut
Sharon E Murphy
Alison Goate
spellingShingle A Joseph Bloom
Maribel Martinez
Li-Shiun Chen
Laura J Bierut
Sharon E Murphy
Alison Goate
CYP2B6 non-coding variation associated with smoking cessation is also associated with differences in allelic expression, splicing, and nicotine metabolism independent of common amino-acid changes.
PLoS ONE
author_facet A Joseph Bloom
Maribel Martinez
Li-Shiun Chen
Laura J Bierut
Sharon E Murphy
Alison Goate
author_sort A Joseph Bloom
title CYP2B6 non-coding variation associated with smoking cessation is also associated with differences in allelic expression, splicing, and nicotine metabolism independent of common amino-acid changes.
title_short CYP2B6 non-coding variation associated with smoking cessation is also associated with differences in allelic expression, splicing, and nicotine metabolism independent of common amino-acid changes.
title_full CYP2B6 non-coding variation associated with smoking cessation is also associated with differences in allelic expression, splicing, and nicotine metabolism independent of common amino-acid changes.
title_fullStr CYP2B6 non-coding variation associated with smoking cessation is also associated with differences in allelic expression, splicing, and nicotine metabolism independent of common amino-acid changes.
title_full_unstemmed CYP2B6 non-coding variation associated with smoking cessation is also associated with differences in allelic expression, splicing, and nicotine metabolism independent of common amino-acid changes.
title_sort cyp2b6 non-coding variation associated with smoking cessation is also associated with differences in allelic expression, splicing, and nicotine metabolism independent of common amino-acid changes.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2013-01-01
description The Cytochrome P450 2B6 (CYP2B6) enzyme makes a small contribution to hepatic nicotine metabolism relative to CYP2A6, but CYP2B6 is the primary enzyme responsible for metabolism of the smoking cessation drug bupropion. Using CYP2A6 genotype as a covariate, we find that a non-coding polymorphism in CYP2B6 previously associated with smoking cessation (rs8109525) is also significantly associated with nicotine metabolism. The association is independent of the well-studied non-synonymous variants rs3211371, rs3745274, and rs2279343 (CYP2B6*5 and *6). Expression studies demonstrate that rs8109525 is also associated with differences in CYP2B6 mRNA expression in liver biopsy samples. Splicing assays demonstrate that specific splice forms of CYP2B6 are associated with haplotypes defined by variants including rs3745274 and rs8109525. These results indicate differences in mRNA expression and splicing as potential molecular mechanisms by which non-coding variation in CYP2B6 may affect enzymatic activity leading to differences in metabolism and smoking cessation.
url http://europepmc.org/articles/PMC3829832?pdf=render
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