rs28399433 — CYP2A6 *9 (TATA box)

Promoter variant that reduces CYP2A6 expression by ~50%, slowing nicotine metabolism and altering response to several cancer and antiretroviral drugs

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CYP2A6*9 — The TATA Box Variant That Slows Nicotine Metabolism

CYP2A6 is the liver enzyme responsible for metabolizing roughly 70–80% of inhaled nicotine, converting it to its primary inactive metabolite cotinine, and then onward to 3-hydroxycotinine. The rate at which someone clears nicotine from their blood is one of the strongest determinants of how much they smoke and whether they will become dependent. CYP2A6*9 is a single nucleotide change in the TATA box11 TATA box
The TATA box is a short DNA sequence in gene promoters where transcription factors bind to initiate RNA production. Changes here alter how many copies of the enzyme the cell makes, without changing the enzyme's structure. of the CYP2A6 promoter — about 48 bases upstream of the transcription start site. This change does not alter the enzyme's amino acid sequence or its catalytic efficiency; instead it reduces how much enzyme is made in the first place.

The Mechanism

CYP2A6 is located on chromosome 19 at position 40,850,474 (GRCh38). The gene is transcribed from the minus strand, so the variant is described as T-48G in coding- strand notation but appears as an A>C change in plus-strand genomic files. Yoshida et al. (2003)22 Yoshida et al. (2003)
Yoshida R et al. Effects of polymorphism in promoter region of CYP2A6 on expression level of mRNA and enzymatic activity in vivo and in vitro. Clin Pharmacol Ther, 2003 demonstrated the mechanism directly: liver tissue from *9 carriers had reduced CYP2A6 mRNA and coumarin 7-hydroxylase activity compared to wild-type, and Korean subjects homozygous for *9 showed a nicotine-to-cotinine ratio of 4.3 — less than half the 10.4 seen in wild-type individuals. The TATA box mutation reduces transcriptional activity by approximately 50%, making this a partial-function allele rather than a null allele like CYP2A6*4 (gene deletion).

The Evidence

A landmark study by Schoedel et al. (2004)33 Schoedel et al. (2004)
Schoedel KA et al. Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians. Pharmacogenetics, 2004 in 356 Caucasian adults showed that genetically slow metabolizers (including *9 carriers) smoked fewer cigarettes per day among dependent smokers (21.3 vs 28.2, P = 0.003) and were significantly less likely to be current smokers at all (OR 0.52, 95% CI 0.29-0.95). The kinetic basis was confirmed by Benowitz et al. (2006)44 Benowitz et al. (2006)
Benowitz NL et al. CYP2A6 genotype and the metabolism and disposition kinetics of nicotine. Clin Pharmacol Ther, 2006, showing *1/*9 carriers have nicotine clearance approximately 80% of wild-type with significantly prolonged half-life.

The treatment implications are counterintuitive. A study by Chen et al. (2014)55 Chen et al. (2014)
Chen LS et al. Pharmacotherapy effects on smoking cessation vary with nicotine metabolism gene CYP2A6. Addiction, 2014 found that standard-dose NRT patches strongly reduced relapse in fast metabolizers (HR 0.39) but not in slow metabolizers (HR 1.09). Slow metabolizers accumulate nicotine from patches more readily: a study by Malaiyandi et al. (2006)66 Malaiyandi et al. (2006)
Malaiyandi V et al. Impact of CYP2A6 genotype on pretreatment smoking behaviour and nicotine levels from NRT. Mol Psychiatry, 2006 found they achieve plasma nicotine levels 44% higher than fast metabolizers on identical patch doses (22.8 vs 15.8 ng/ml, P = 0.02). This suggests slow metabolizers may receive excessive nicotine replacement from standard-dose NRT. A comprehensive systematic review by Jones et al. (2022)77 Jones et al. (2022)
Jones SK et al. Nicotine metabolism predicted by CYP2A6 genotypes in relation to smoking cessation. Nicotine Tob Res, 2022 confirmed that untreated slow metabolizers of European ancestry have approximately doubled odds of quitting (OR 2.05, 95% CI 1.23-3.42) — an advantage that pharmacotherapy attenuates, not enhances.

Beyond nicotine, CYP2A6 activates the prodrug tegafur88 tegafur
Tegafur is an oral fluoropyrimidine prodrug; CYP2A6 converts it to 5-fluorouracil, the active cytotoxic agent. Slow metabolizers produce less 5-FU and may have reduced antitumour efficacy. to 5-fluorouracil, metabolizes the aromatase inhibitor letrozole, contributes to efavirenz clearance, and catalyzes coumarin 7-hydroxylation. Slow metabolizers should have these substrate drugs reviewed by their oncologist or pharmacist.

Practical Implications

For smokers: slow CYP2A6 metabolizers naturally smoke less and are more likely to quit unaided. Standard-dose nicotine patches may over-deliver nicotine; a lower-dose patch (7 mg rather than 21 mg) or varenicline — which does not depend on nicotine metabolism — may be better-matched. For cancer patients: inform your oncologist before starting tegafur-based regimens. For general health monitoring: measure the 3-hydroxycotinine/cotinine ratio if precise metabolizer phenotyping is needed for clinical decisions.

Interactions

CYP2A6*9 commonly co-occurs with other reduced-function alleles CYP2A6*2 (rs1801272, missense Leu160His) and CYP2A6*4 (gene deletion). Compound carriers of *9 with *2 or *4 on the other chromosome (compound heterozygotes) have substantially lower nicotine clearance than *9 heterozygotes alone, approaching the poor-metabolizer phenotype. The nicotine metabolism ratio (3-hydroxycotinine/ cotinine in urine) integrates across all CYP2A6 alleles and provides a direct phenotypic measure independent of genotype.

Drug Interactions

nicotine dose_adjustment literature
tegafur increased_toxicity literature
letrozole dose_adjustment literature
coumarin dose_adjustment literature
efavirenz dose_adjustment literature
dexmedetomidine increased_toxicity literature

Genotype Interpretations

What each possible genotype means for this variant.

AA Normal Metabolizer Normal

Normal CYP2A6 activity — standard nicotine and drug metabolism

You have two copies of the standard CYP2A6 promoter. Your CYP2A6 enzyme is produced at normal levels, and you metabolize nicotine at the expected rate. About 81% of people globally share this genotype, and it is found in approximately 86% of Europeans.

Standard-dose nicotine replacement therapies (patches, gum, lozenge) are calibrated for your metabolism rate. If you smoke, standard pharmacotherapy guidelines apply to you without genotype-based adjustments.

AC Intermediate Metabolizer Intermediate

One CYP2A6*9 copy — moderately reduced nicotine metabolism

The single *9 allele reduces CYP2A6 transcriptional output by roughly 50% on that chromosome, giving you one normal-output and one reduced-output copy. Kinetic studies place *1/*9 carriers at about 80% of wild-type nicotine clearance. This is clinically meaningful: the 3-hydroxycotinine/cotinine ratio (a direct measure of CYP2A6 activity in urine) is shifted toward the slow end in carriers compared to *1/*1 individuals.

The smoking behavior data are consistent: slow metabolizers average about 7 fewer cigarettes per day among dependent smokers and are 48% less likely to be current smokers in cross-sectional studies (OR 0.52). With a slightly higher baseline nicotine exposure per cigarette, the reinforcing effect of each cigarette may be muted, reducing escalation of use.

For NRT, the Malaiyandi et al. study found slow metabolizers achieve 44% higher plasma nicotine from identical patch doses. A lower-strength patch (14 mg or 7 mg instead of 21 mg) may be more appropriate to avoid side effects from nicotine excess (nausea, dizziness, sleep disturbance).

CC Poor Metabolizer Poor

Two CYP2A6*9 copies — substantially reduced nicotine metabolism

With both TATA box alleles mutated, transcription of CYP2A6 is reduced approximately 50-60% in homozygous carriers compared to *1/*1. In the Yoshida et al. 2003 study, homozygous *9/*9 Koreans showed a nicotine-cotinine ratio of 4.3 ± 2.4 versus 10.4 ± 9.2 in wild-type (p < 0.005), indicating substantially impaired nicotine clearance. This places *9/*9 individuals well into the pharmacogenomic poor-metabolizer range, though still above the essentially zero activity of *4/*4 homozygotes (gene deletion).

For cancer pharmacotherapy, the implications are significant. Tegafur requires CYP2A6 for conversion to 5-fluorouracil (5-FU). Poor CYP2A6 metabolizers may produce insufficient 5-FU from tegafur-based oral chemotherapy (e.g., UFT, S-1), potentially reducing tumour response. Letrozole (an aromatase inhibitor for breast cancer) is primarily cleared by CYP2A6 and CYP3A4; poor CYP2A6 metabolizers may accumulate higher letrozole plasma levels. Efavirenz (antiretroviral) is also a CYP2A6 substrate; reduced clearance may increase efavirenz exposure and central nervous system side effects.