NAT2 N-acetyltransferase 2
NAT2 inactivates drugs by acetylation.
What does NAT2 do?
NAT2 inactivates drugs by acetylation. Its common haplotypes split people into rapid, intermediate and slow acetylators, and the split is strongly population-dependent: about half of Europeans and South Asians are slow acetylators, against roughly one in ten East Asians. Slow acetylators clear isoniazid, hydralazine, sulfasalazine, dapsone and procainamide more slowly and are more prone to their toxicities, from isoniazid liver injury to hydralazine-induced lupus.
What do the NAT2 metaboliser phenotypes mean?
Each person carries two NAT2 alleles. Each allele has a function and an activity score; the two scores are added and the total is mapped to a phenotype as follows.
| Phenotype | How it is assigned | What it means |
|---|---|---|
| Rapid Acetylator | two rapid alleles (e.g. *4/*4) | Fast inactivation: lower drug exposure at a standard dose. |
| Intermediate Acetylator | one rapid and one slow allele | Intermediate clearance. |
| Slow Acetylator | two slow alleles (e.g. *5B/*6A) | Slow inactivation: higher exposure and higher risk of dose-related toxicity. |
Which NAT2 star alleles are there, and how common are they?
| Allele | Function | Activity score | Defining variants | Frequency (EUR / EAS / AFR / SAS / AMR) | Note |
|---|---|---|---|---|---|
| *4 | rapid acetylation | – | reference | 23.0% / 45.0% / 25.0% / 30.0% / 28.0% | Wild-type reference allele. All 7 SNP positions carry the reference nucleotide. Associated with rapid acetylation. |
| *12A | rapid acetylation | – | rs1208 c.803A>G (K268R) | 2.0% / 1.0% / 3.0% / 2.0% / 2.0% | Rapid acetylator allele. K268R variant does not significantly reduce enzyme activity. Now designated as NAT2*1 in PharmVar. |
| *12B | rapid acetylation | – | rs1041983 c.282C>T (Y94= (synonymous)) rs1208 c.803A>G (K268R) | 1.0% / 2.0% / 2.0% / 1.0% / 1.0% | Rapid acetylator allele. Combination of synonymous Y94= and K268R variants. |
| *12C | rapid acetylation | – | rs1799929 c.481C>T (L161= (synonymous)) rs1208 c.803A>G (K268R) | 2.0% / 1.0% / 1.0% / 1.0% / 2.0% | Rapid acetylator allele. Combination of synonymous L161= and K268R variants. |
| *13 | rapid acetylation | – | rs1041983 c.282C>T (Y94= (synonymous)) | 2.0% / 25.0% / 8.0% / 10.0% / 5.0% | Rapid acetylator allele. Synonymous Y94= variant only. Common in East Asian populations (~25%). |
| *5A | slow acetylation | – | rs1801280 c.341T>C (I114T) rs1799929 c.481C>T (L161= (synonymous)) | 2.0% / 1.0% / 2.0% / 2.0% / 2.0% | Slow acetylator allele. I114T is the primary functional variant causing reduced enzyme activity. |
| *5B | slow acetylation | – | rs1801280 c.341T>C (I114T) rs1799929 c.481C>T (L161= (synonymous)) rs1208 c.803A>G (K268R) | 30.0% / 2.0% / 22.0% / 15.0% / 20.0% | Most common slow acetylator allele globally. Predominant in European (~30%) and African (~22%) populations. I114T drives the functional impact. |
| *5C | slow acetylation | – | rs1801280 c.341T>C (I114T) rs1208 c.803A>G (K268R) | 1.0% / 1.0% / 2.0% / 1.0% / 1.0% | Slow acetylator allele. I114T + K268R combination. |
| *5D | slow acetylation | – | rs1801280 c.341T>C (I114T) | 1.0% / 0.5% / 1.0% / 1.0% / 1.0% | Slow acetylator allele. I114T variant alone. |
| *5E | slow acetylation | – | rs1801280 c.341T>C (I114T) rs1799930 c.590G>A (R197Q) | 0.5% / 0.5% / 0.5% / 0.5% / 0.5% | Slow acetylator allele. Combination of two functional variants I114T + R197Q. |
| *6A | slow acetylation | – | rs1041983 c.282C>T (Y94= (synonymous)) rs1799930 c.590G>A (R197Q) | 25.0% / 20.0% / 10.0% / 18.0% / 15.0% | Second most common slow acetylator allele. Common across all populations. R197Q is the primary functional variant. |
| *6B | slow acetylation | – | rs1799930 c.590G>A (R197Q) | 1.0% / 2.0% / 3.0% / 2.0% / 2.0% | Slow acetylator allele. R197Q variant alone. |
| *6C | slow acetylation | – | rs1041983 c.282C>T (Y94= (synonymous)) rs1799930 c.590G>A (R197Q) rs1208 c.803A>G (K268R) | 0.5% / 0.5% / 0.5% / 0.5% / 0.5% | Slow acetylator allele. R197Q + K268R + Y94= combination. |
| *7A | slow acetylation | – | rs1799931 c.857G>A (G286E) | 0.5% / 3.0% / 0.5% / 1.0% / 0.5% | Slow acetylator allele. G286E variant. More common in East Asian populations. |
| *7B | slow acetylation | – | rs1041983 c.282C>T (Y94= (synonymous)) rs1799931 c.857G>A (G286E) | 1.0% / 12.0% / 1.0% / 3.0% / 2.0% | Most common slow acetylator allele in East Asian populations (~12%). G286E is the primary functional variant. Y94= is a tagging SNP. |
| *14A | slow acetylation | – | rs1801279 c.191G>A (R64Q) | 1.0% / 0.1% / 8.0% / 2.0% / 3.0% | Slow acetylator allele. R64Q variant. Most common in African populations (~8%). Rare in East Asians. |
| *14B | slow acetylation | – | rs1801279 c.191G>A (R64Q) rs1041983 c.282C>T (Y94= (synonymous)) | 0.5% / 0.1% / 5.0% / 1.0% / 2.0% | Slow acetylator allele. R64Q + Y94= combination. Predominantly found in African populations. |
| *14C | slow acetylation | – | rs1801279 c.191G>A (R64Q) rs1041983 c.282C>T (Y94= (synonymous)) rs1208 c.803A>G (K268R) | 0.5% / 0.1% / 3.0% / 0.5% / 1.0% | Slow acetylator allele. R64Q + Y94= + K268R combination. |
Which drugs does NAT2 affect?
- Isoniazid Anti-tuberculosis CPIC level A
- Isoniazid is inactivated by NAT2 acetylation. Slow acetylators accumulate more of the hepatotoxic intermediate and have a several-fold higher rate of drug-induced liver injury.
- Hydralazine Antihypertensive (vasodilator) CPIC level A
- Hydralazine is cleared by NAT2. Slow acetylators have higher exposure and a much higher rate of drug-induced lupus with prolonged use.
- Sulfasalazine Anti-inflammatory (DMARD) CPIC level B
- The sulfapyridine released from sulfasalazine is cleared by NAT2. Slow acetylators have more dose-related side effects such as nausea, headache and haemolysis.
- Procainamide Antiarrhythmic CPIC level B
- Procainamide is acetylated by NAT2. Slow acetylators develop procainamide-induced lupus more often and sooner.
- Dapsone Anti-infective / Anti-inflammatory CPIC level C
- Dapsone is partly cleared by NAT2. Slow acetylators are more prone to its haematological toxicity.
- Caffeine Stimulant (methylxanthine) CPIC level D
- Caffeine is the standard probe drug for NAT2 phenotyping: the ratio of its acetylated metabolites in urine reveals acetylator status. Genotype and phenotype agree in most people.
Can a 23andMe or AncestryDNA file tell you your NAT2 type?
NAT2 haplotypes are inferred from a panel of seven coding SNPs; consumer chips usually carry the four that define the common slow alleles (rs1801279, rs1801280, rs1799930, rs1799931). Phase — which variants sit on the same chromosome — is not observed directly, so the diplotype is a statistical inference.
Upload your 23andMe, AncestryDNA or WeGene raw file → · Ask G2: “What is my NAT2 metaboliser status and which of my medicines does it affect?”
Genetic associations describe risk across populations, not a diagnosis for any one person. Most variants shift risk modestly and act alongside lifestyle, environment and other genes. Consumer DNA chips do not read every position and can be wrong at any single one. For general education only; talk to a clinician or genetic counsellor before acting on anything here, and never change a prescribed medicine without your prescriber.