Identification and Characterization of Novel CYP2A6 Variants in African American Slow Nicotine Metabolizers
Year: 2014
Type: dissertation
Abstract: Nicotine, the main addictive compound in tobacco, is metabolically inactivated to cotinine primarily by the hepatic enzyme CYP2A6. Substantial genetic variation in the CYP2A6 gene contributes to large variation in nicotine metabolism which alters numerous smoking behaviours. The goal of this study was to identify and characterize novel CYP2A6 variants. The CYP2A6 gene from African American phenotypically slow nicotine metabolizers was sequenced. Seven novel non-synonymous variants were identified: 468G>A (V68M), 1767C>G (I149M), 3515G>A (R265Q), 3524T>C (I268T), 4406C>T (T303I), 5661G>A (E390K), 6531T>C (L462P). They were introduced into a cDNA expression construct where they displayed lower protein expression, reduced nicotine metabolism to cotinine, and/or reduced stability as evaluated by western blotting and enzymatic activity. Genotyping assays were developed and assessed in 512 African Americans. Allelic frequencies ranged from 0.1-0.6% with a collective genotype frequency of 3.2%. Here we identified novel variants with reduced/loss of CYP2A6 activity, increasing our understanding of CYP2A6 variability.
Source: TSpace (University of Toronto)
Author: Mark Piliguian
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2729993432