CYP2A6 – Nicotine Dependence

CYP2A6 is the primary human enzyme responsible for hepatic nicotine C-oxidation and influences systemic nicotine clearance. A case-cohort genotyping study of 120 smokers demonstrated that the CYP2A6*4 whole-gene deletion is closely associated with increased risk of nicotine dependence, as deletion carriers exhibited higher dependence scores compared with individuals carrying one or two functional copies (n=120) (PMID:25446842). In vitro and in vivo functional assays of missense variants, notably c.1412T>C (p.Ile471Thr), reveal severely reduced enzyme stability and nicotine C-oxidation activity, corresponding to significantly lower cotinine/nicotine metabolic ratios in human and Escherichia coli expression systems (PMID:11237731). Together, genetic association data are limited to a single cohort without familial segregation or independent replication, while functional evidence is moderate and concordant across multiple model systems. Conflicting evidence is minimal, though population-specific allele frequencies and linkage with CYP2A7 complicate interpretation of genotype–phenotype correlations. Additional large-scale, multi-ethnic association studies and segregation analyses are required to strengthen the clinical validity of CYP2A6 as a biomarker for nicotine dependence.

Key Take-Home: CYP2A6 genotyping, particularly for copy number and key missense alleles, holds promise for predicting nicotine dependence risk and tailoring smoking-cessation therapies.

References

• Experimental and molecular pathology • 2014 • Single tube genotyping of CYP2A6 gene deletion based on copy number determination by quantitative real-time PCR. PMID:25446842
• Biochemical and biophysical research communications • 2001 • A novel single nucleotide polymorphism altering stability and activity of CYP2a6. PMID:11237731

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