rs28399444 — CYP2A6 *7 (I471T)

CYP2A6*7 — The Near-Silent Nicotine Enzyme

CYP2A6¹¹ CYP2A6
Cytochrome P450 2A6, the main enzyme converting nicotine to cotinine in the liver is responsible for approximately 80–90% of nicotine's metabolic clearance. The CYP2A6*7 allele carries a missense mutation — isoleucine to threonine at codon 471 — that produces a dramatically unstable enzyme with near-zero nicotine-metabolizing activity. While this allele is rare in most populations (<1%), it reaches 6–15% frequency in East Asian populations, making it clinically relevant for a substantial portion of people with Japanese, Korean, or Chinese ancestry.

The Mechanism

The c.1412T>C variant²² c.1412T>C variant
nucleotide change on the coding strand; A>G on the plus strand at chr19:40843869 substitutes threonine for isoleucine at position 471 in the CYP2A6 protein. This amino acid change occurs in a region critical for heme coordination and structural stability, causing remarkable reduction of holoenzyme stability at body temperature³³ remarkable reduction of holoenzyme stability at body temperature
Ariyoshi N et al. Drug Metab Dispos, 2001. The result is an enzyme that almost entirely lacks nicotine C-oxidase activity⁴⁴ almost entirely lacks nicotine C-oxidase activity
the primary reaction that converts nicotine to cotinine, measured as cotinine/nicotine ratio while paradoxically retaining partial coumarin 7-hydroxylase activity. This substrate-selective loss of function reflects the different binding orientations of the two substrates within the enzyme active site.

The Evidence

A Japanese/Korean phenotyping study⁵⁵ Japanese/Korean phenotyping study
Yoshida R et al. Br J Clin Pharmacol, 2002 in 301 subjects measured plasma nicotine and cotinine concentrations after a standardized nicotine gum dose. All five individuals with impaired metabolism carried either CYP2A6*7 or CYP2A6*4, confirming that CYP2A6*7 alone causes meaningful in vivo metabolic impairment. The allele frequency was 6.5% in Japanese and 3.6% in Korean subjects.

Population-level consequences are measurable. Schoedel et al. Pharmacogenetics, 2004⁶⁶ Schoedel et al. Pharmacogenetics, 2004 compared 375 smokers to 224 non-smokers, finding that slow metabolizers consumed approximately 21.3 cigarettes/day versus 28.2 for normal metabolizers (p = 0.003) and were significantly underrepresented among nicotine-dependent smokers (OR 0.52; 95% CI 0.29–0.95).

For oncology, letrozole (an aromatase inhibitor used in breast cancer) is substantially cleared by CYP2A6. A study of 284 breast cancer patients found >10-fold interpatient variability in letrozole plasma concentrations strongly associated with CYP2A6 genotype⁷⁷ >10-fold interpatient variability in letrozole plasma concentrations strongly associated with CYP2A6 genotype
Desta Z et al. Clin Pharmacol Ther, 2011 (p < 0.0001). A larger 617-patient pharmacokinetic study confirmed CYP2A6 slow metabolizers have 46% lower apparent letrozole clearance⁸⁸ CYP2A6 slow metabolizers have 46% lower apparent letrozole clearance
Puszkiel A et al. Eur J Pharm Sci, 2024 compared to normal metabolizers, predicting substantially elevated drug exposure.

For tegafur (a prodrug converted to 5-fluorouracil by CYP2A6), in vitro characterization of recombinant CYP2A6*7 enzyme demonstrated markedly lower Vmax values⁹⁹ demonstrated markedly lower Vmax values
Yamamiya I et al. Drug Metab Dispos, 2014 for both enantiomers versus wild-type, suggesting reduced prodrug activation in carriers.

Practical Actions

Carriers of CYP2A6*7 metabolize nicotine slowly. In practical terms, this means nicotine lingers longer in the body after each cigarette, reducing the urge to smoke again quickly. Slow metabolizers naturally smoke fewer cigarettes and become less deeply dependent. However, the cessation picture is nuanced: nicotine replacement therapy may be less effective for slow metabolizers¹⁰¹⁰ nicotine replacement therapy may be less effective for slow metabolizers
Chen LS et al. Biol Psychiatry, 2014 because NRT works partly by maintaining steady nicotine levels to suppress withdrawal — but slow metabolizers already clear nicotine slowly, so the patch's advantage is attenuated. Non-nicotine cessation approaches (varenicline, bupropion) are unaffected by CYP2A6 status.

For letrozole treatment, elevated drug exposure from slow CYP2A6 metabolism may increase the risk of musculoskeletal side effects (arthralgia, myalgia) that are dose-dependent. Prescribers managing breast cancer patients with CYP2A6*7 should be aware that standard doses will produce higher circulating letrozole concentrations.

Interactions

CYP2A6 activity is additive across alleles. Carriers of one CYP2A6*7 allele plus another reduced-function allele (such as rs1801272 CYP2A6*2, rs28399463 CYP2A6*5, or the deletion allele CYP2A6*4) may have near-complete loss of CYP2A6 activity — a compound heterozygote phenotype equivalent to a null metabolizer. The nicotine metabolite ratio (3′-hydroxycotinine to cotinine) is a reliable functional biomarker of overall CYP2A6 activity and can guide cessation treatment selection independently of genotype.