rs1801272 — CYP2A6 *2 (L160H)

CYP2A6*2 — The Nicotine Slow-Burn Variant

Your liver converts nicotine to cotinine in minutes. The enzyme doing this work — CYP2A6 — is encoded by one of the most polymorphic drug-metabolism genes in the human genome. The CYP2A6*2 allele¹¹ CYP2A6*2 allele
rs1801272, also called L160H or Leu160His swaps a single amino acid at position 160 of the protein, replacing leucine with histidine. The result: the enzyme is catalytically dead. People carrying this variant metabolize nicotine far more slowly than average — and the downstream consequences touch everything from smoking behaviour to cancer risk to dosing of several unrelated drugs.

The Mechanism

CYP2A6 is responsible for roughly 70–80% of hepatic nicotine clearance, converting nicotine to its primary metabolite cotinine²² cotinine
half-life ~16 hours; used as a biomarker for tobacco exposure. The L160H substitution disrupts the haem-binding domain of the enzyme, abolishing catalytic activity entirely. Heterozygous carriers (*1/*2) have approximately 50% reduced activity; homozygous carriers (*2/*2) have essentially zero CYP2A6 function via this pathway. Because CYP2A6 also handles ~20% of CYP2B6-independent nicotine metabolism and the bulk of cotinine further oxidation to 3-hydroxycotinine³³ ~20% of CYP2B6-independent nicotine metabolism and the bulk of cotinine further oxidation to 3-hydroxycotinine, the impact cascades across the entire nicotine-clearance pathway.

Beyond nicotine, CYP2A6 is the primary metaboliser of coumarin (the fragrance compound), the aromatase inhibitor letrozole, the prodrug tegafur (activated to 5-fluorouracil), and contributes meaningfully to efavirenz and valproic acid clearance. Poor metabolisers of this enzyme are not just slow smokers — they are pharmacokinetically different across a clinically significant drug panel.

The Evidence

The smoking-cessation advantage of slow metabolisers is well-documented. A systematic review of 34 studies⁴⁴ systematic review of 34 studies
Jones et al. Nicotine Tob Res, 2022 found that reduced-function CYP2A6 carriers had more than twice the odds of quitting unaided compared to normal metabolisers (OR 2.05, 95% CI 1.23–3.42) in European ancestry populations. The mechanism: when nicotine lingers longer in plasma, its aversive and satiating effects are amplified, and the urge to re-dose is suppressed.

Reduced carcinogen activation is a parallel benefit. CYP2A6 activates tobacco-specific nitrosamines (TSNA) — including NNK, a potent lung carcinogen — as well as polycyclic aromatic hydrocarbons. A nested case-control study of 325 lung cancer cases⁵⁵ nested case-control study of 325 lung cancer cases
Yuan et al. Int J Cancer, 2016 in Chinese men found poor metabolisers had an odds ratio of 0.64 for lung cancer, largely mediated by lower carcinogen-equivalent intake. A similar pattern has been observed in other Asian cohorts with high frequencies of CYP2A6 null alleles.

The picture is inverted for nicotine replacement therapy (NRT). When nicotine is delivered externally and continuously (patch, gum, lozenge), the slow-clearance advantage disappears: nicotine accumulates more, side effects (nausea, palpitations, insomnia) become more prominent, and the cessation benefit narrows. The 2022 meta-analysis⁶⁶ 2022 meta-analysis reported that with NRT, the cessation benefit was attenuated; with bupropion, intermediate/slow metabolisers actually showed worse outcomes (OR 0.86, 95% CI 0.79–0.94).

Practical Actions

For smokers: the natural tendency in poor metabolisers is to smoke fewer cigarettes per day and to find quitting easier — align with this biology rather than against it. If NRT is used, lower-dose formulations are appropriate; standard doses may cause accumulation and side effects. Varenicline (Champix/Chantix) is not primarily metabolised by CYP2A6 and is not affected.

For non-smoking contexts, this variant has direct drug-dosing implications. Letrozole (used for breast cancer and fertility), tegafur (colorectal cancer prodrug), and efavirenz (HIV therapy) all require attention when CYP2A6 activity is absent. Standard doses may result in elevated exposure; discuss genotype-informed dosing with oncology or infectious-disease prescribers.

Interactions

CYP2A6 activity is also influenced by other variants in the same gene. The CYP2A6 deletion alleles (*4A, *4B, *4C, *4D) completely eliminate one gene copy and are most common in East Asian populations. Compound heterozygotes carrying *2 on one chromosome and a deletion on the other are effectively null metabolisers. Other partial-activity alleles (*7, *10, *12, *17) can compound the effect in trans. Full phenotype prediction requires haplotype-based analysis (e.g. PharmCAT or star-allele calling) rather than individual SNP calls. Related variants rs28399433 (*4 deletion tag) and rs5031016 (*7) are relevant for East Asian ancestry individuals in particular.