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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.

plos one

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