rs1801280 — NAT2 I114T

NAT2 I114T - Your Detoxification Speed

N-acetyltransferase 2 (NAT2) is a Phase II ¹¹ Phase II detoxification conjugates reactive intermediates from Phase I with small molecules to make them water-soluble and excretable detoxification enzyme that adds an acetyl group to aromatic amines and hydrazines, making them water-soluble so your body can excrete them. These substrates include environmental carcinogens from cigarette smoke, heterocyclic amines ²² Heterocyclic amines are carcinogenic compounds formed when meat is cooked at high temperatures, especially charring or grilling from cooked meat, and medications like isoniazid (tuberculosis treatment) and sulfasalazine.

The Mechanism

The I114T variant (rs1801280) changes isoleucine to threonine at position 114 of the NAT2 protein. The C allele (Thr) destabilizes the enzyme, leading to faster degradation and lower acetylation capacity. This is one of the most common "slow acetylator" alleles in European populations, characterizing the NAT2*5B haplotype. The C allele frequency is remarkably high in Europeans (~44%) but very rare in East Asians (~3%).

Slow vs. Rapid Acetylators

NAT2 acetylator status is determined by the combination of multiple variants (rs1801280, rs1799930, rs1208). You need two slow alleles (one from each parent) to be a slow acetylator. About 50-60% of Europeans are slow acetylators ³³ This high frequency suggests slow acetylation may have been advantageous in certain ancestral environments due to the high frequency of these variants, compared to only 10-20% of East Asians.

Clinical Significance

Slow acetylators have increased risk of bladder cancer from occupational exposure to aromatic amines. A major meta-analysis⁴⁴ major meta-analysis
Garcia-Closas M et al. NAT2 slow acetylation and bladder cancer risk. Lancet, 2005 found an overall OR of 1.4 (95% CI 1.2-1.7) for bladder cancer in slow acetylators, with stronger effects in cigarette smokers. Slow acetylators also require dose adjustments for isoniazid and are more prone to drug-induced lupus from certain medications. However, slow acetylation may actually be protective in some contexts - rapid acetylators have higher colorectal cancer risk from heterocyclic amines in well-done meat.

Practical Advice

If you are a slow acetylator: minimize exposure to cigarette smoke (active and secondhand), moderate consumption of heavily charred or grilled meats, and inform your doctor of your acetylator status if prescribed isoniazid or other NAT2 substrate medications.